WO2022167664A1 - Composés comprenant une fraction tétrapeptidique - Google Patents

Composés comprenant une fraction tétrapeptidique Download PDF

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WO2022167664A1
WO2022167664A1 PCT/EP2022/052908 EP2022052908W WO2022167664A1 WO 2022167664 A1 WO2022167664 A1 WO 2022167664A1 EP 2022052908 W EP2022052908 W EP 2022052908W WO 2022167664 A1 WO2022167664 A1 WO 2022167664A1
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compound
crystal
moiety
drug
seq
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PCT/EP2022/052908
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Nele KINDT
Geert REYNS
Andrea CASAZZA
Lawrence Van Helleputte
Olivier Defert
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Cobiores Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu

Definitions

  • the present invention relates to the field of compounds intended for the treatment of cancer. Selectivity of these compounds is gained through the presence of a specific tetrapeptidic moiety allowing selective release of the drug.
  • the drug in particular is a cytostatic, cytotoxic, or anti-cancer drug.
  • a protective capping group can be introduced to ensure stability of the compound in blood.
  • the tetrapeptidic moieties provide to prodrug compounds a selectivity index of at least 2 for at least 2 different types of cancers (compared to normal cells).
  • chemotoxic drugs A major problem in the use of chemotoxic drugs is their low selectivity for cancer cells resulting in dose limiting and life threatening toxic side effects. The most common acute toxicity is myelotoxicity resulting in a severe leukopenia and thrombocytopenia. Some of the commonly used drugs have also a more specific toxicity. Doxorubicin (Dox), an anthracycline drug, is an example of such a chemotoxic drug that induces besides severe myelotoxicity a severe cardiotoxicity. These toxicities restrict its use above a cumulative dose of 500 mg/m 2 .
  • Dox an anthracycline drug
  • oligopeptidic prodrug conjugation with (i) a tumor-recognizing or tumor-targeting molecule (e.g. receptor ligand; see, e.g., Safavy et al. 1999 -J Med Chem 42,4919- 4924) or with (ii) a peptide that is cleaved preferentially in the immediate vicinity of tumor cells by proteases preferentially secreted or produced by tumor cells ("oligopeptidic prodrug").
  • a tumor-recognizing or tumor-targeting molecule e.g. receptor ligand; see, e.g., Safavy et al. 1999 -J Med Chem 42,4919- 4924
  • oligopeptidic prodrug e.g., a peptide that is cleaved preferentially in the immediate vicinity of tumor cells by proteases preferentially secreted or produced by tumor cells
  • Tumor-specific oligopeptidic prodrugs such as prodrugs of doxorubicin
  • the prodrug-activating peptidases are not necessarily tumor specific but can increase the drug selectivity to the extent that these peptidases are (selectively) oversecreted in the extracellular space of solid tumors and play an important role in cancer cell invasion and metastasis.
  • N-succinyl-beta-alanyl-L- leucyl-L-alanyl-L-leucyl-doxorubicin (Suc-PALAL-dox or DTS-201) was selected as such a candidate prodrug (Fernandez et al. 2001, J Med Chem 44:3750-3).
  • this prodrug is, in mice, about 5 times, and in dogs, 3 times less toxic.
  • Chronic treatment with Suc- ALAL-dox proved to be significantly less cardiotoxic than with Dox at doses up to 8-fold higher in rats.
  • the improved activity of Suc-PALAL-dox over Dox was observed in several tumor xenograft models (Dubois et al. 2002, Cancer Res 62:2327-31; Ravel et al. 2008, Clin Cancer Res 14:1258-65).
  • W002/100353 specifically discloses chemotherapeutic prodrugs designed with a 3- to 6-amino acid oligopeptide cleavable by CD10.
  • W002/00263 discloses prodrugs with a 3-amino acid oligopeptide cleavable byTHOPl and at least 1 prodrug with an amino acid oligopeptide (Leu-Ala-Gly) not cleavable by CD10.
  • WOOO/33888 and WOOl/95945 disclose prodrugs with a 4- to 20-amino acid oligopeptide comprising a non-genetically encoded (non-natural) amino acid at a fixed position, with said oligopeptide being cleavable by THOPl.
  • WOOl/95945 At least 1 prodrug, with a PAIa-Leu-Tyr-Leu oligopeptide, was reported to be resistant to CD10 proteolytic action.
  • WOOl/95943 discloses prodrugs with a 3- to 4-amino acid oligopeptide comprising a fixed isoleucine, said oligopeptide preferably being resistant to THOP1; no information on CDlO-susceptibility or -resistance is given.
  • a more general concept of a prodrug consisting of a drug linked to an oligopeptide (of at least 2 amino acids) itself linked to a terminal group is disclosed in WO96/05863 and was later extended in WOOl/91798.
  • non-drug moiety is at least comprising a water-soluble polymer and a peptide (comprising 4 to 5 natural or non-natural amino acids) selectively cleavable by action of matrix metalloproteinases (MMPs)
  • MMPs matrix metalloproteinases
  • W002/38590, WO03/094972, WO2014/062587 and US2014/0087991 focus on anti-tumor prodrugs that are activatable by the human fibroblast activation protein (FAPa); the prodrug comprises an oligopeptide of 4 to 9 amino acids with a cyclic amino acid at a fixed position.
  • WO99/28345 discloses prodrugs that are proteolytically cleavable by prostate-specific antigen (PSA) in the oligopeptide of less than 10 amino acids present in the prodrug.
  • PSA prostate-specific antigen
  • WO97/34927 revealed the FAPa-scissable prodrugs Ala-Pro-7-amino-4-trifluoromethylcoumarin and Lys-Pro-7-amino-4-trifluoromethylcoumarin.
  • WOOO/71571 focuses on FAPa-scissable prodrugs, with some further experimental investigations on proteolytic sensitivity to CD26 (dipeptidylpeptidase IV).
  • Other prodrugs activatable by FAPa include prodrugs of the promellitin toxin (LeBeau et al. 2009, Mol Cancer Ther 8, 1378-1386), prodrugs of doxorubicin (Huang et al.
  • WOOl/68145 discloses MMP-cleavable but neprilysin (CDlO)-resistant doxorubicin prodrugs (see Example 1001 therein) comprising a 3- to 8-amino acid oligopeptide.
  • Metalloproteinase- and plasminsensitive doxorubicin prodrugs have been developed, as well as CNGRC-peptide conjugates with doxorubicin (Hu et al. 2010, Bioorg Med Chem Lett 20, 853-856; Chakravarty et al. 1983, J Med Chem 26, 638-644; Devy et al. 2004, FASEB J 18, 565-567; Vanhensbergen et al. 2002, Biochem Pharmacol 63, 897-908).
  • WO97/12624, WO97/14416, WO98/10651, WO98/18493 and WO99/02175 disclose peptide- comprising prodrugs wherein the peptide is cleavable by the prostate-specific antigen (PSA).
  • PSA prostate-specific antigen
  • W02014/102312 describes prodrugs comprising tetrapeptides that are cleaved in 2 steps by at least 2 different peptidases enriched in the vicinity of tumor cells. Such 2-step activation increased drug selectivity.
  • Disclosed tetrapeptides cleavable by LS174T tumor cell-conditioned medium were ALGP, KLGP and TSGP; at the same time W02014/102312 clarified that other XXGP tetrapeptides included in a similar constellation in a prodrug are not cleaved by LS174T tumor cell-conditioned medium, thus indicating that the "XX" amino acids cannot be randomly chosen.
  • prodrugs are the presence of a protecting or capping moiety, usually covalently linked to the N-terminal side of the oligopeptide, which adds to the stability of the prodrug and/or adds to the prevention of internalization of the prodrug into a cell such as a target cell.
  • protecting or capping moieties include non-natural amino acids, p-alanyl or succinyl groups (e.g. WO96/05863, US 5,962,216).
  • Further stabilizing, protecting or capping moieties include diglycolic acid, maleic acid, pyroglutamic acid, glutaric acid, (e.g., WOOO/33888), a carboxylic acid, adipic acid, phthalic acid, fumaric acid, naphthalene dicarboxylic acid, 1,8-naphtyldicarboxylic acid, aconitic acid, carboxycinnamic acid, triazole dicarboxylic acid, butane disulfonic acid, polyethylene glycol (PEG) or an analog thereof (e.g., WOOl/95945), acetic acid, 1- or 2-naphthylcarboxylic acid, gluconic acid, 4- carboxyphenyl boronic acid, polyethylene glycolic acid, nipecotic acid, and isonipecotic acid (e.g., W002/00263, W002/100353), succinylated polyethylene glycol (e.g
  • W02008/120098 A new type of protecting or capping moiety was introduced in W02008/120098, being a 1,2, 3, 4 cyclobutanetetracarboxylic acid.
  • the protecting or capping moiety in W002/07770 may be polyglutamic acid, carboxylated dextranes, carboxylated polyethylene glycol or a polymer based on hydroxyprolyl-methacrylamide or N-(2-hydroxyprolyl)methacryloylamide.
  • W02014/102312 introduced phosphonoacetyl-, and further used the previously known succinyl group, as a capping group or capping moiety.
  • OP is selected from the group consisting of AAGP (SEQ ID NO:4); AVGP (SEQ ID NO:5); MLGP (SEQ ID NO:6); NLGP (SEQ ID NO:7); IAGP (SEQ ID NO:8); LAGP (SEQ ID NO:9); and VAGP (SEQ ID NQ:10);
  • D is a drug; or a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph, isomer, or amorphous form of said compound.
  • said drug D is a cytotoxic drug, a cytostatic drug, or is an anti-cancer drug.
  • the linkage between OP and D is direct, or is indirect via a linker or spacing group.
  • the linkage between C and OP is direct, or is indirect via a linker or spacing group.
  • both linkage between OP and D and linkage between C and OP are direct, or are indirect via a linker or spacing group.
  • such linker or spacing group is a self-eliminating linker or spacing group.
  • any of the above compounds, salt, crystal, co-crystal, polymorph, isomer or amorphous form thereof, is further complexed with a macrocyclic moiety.
  • compositions comprising any one of the compound, salt thereof, crystal thereof, co-crystal comprising it, or polymorph, isomer or amorphous form of said compound.
  • Such composition may further comprise at least one of a pharmaceutically acceptable solvent, diluent or carrier, such as to form e.g. a pharmaceutically acceptable composition.
  • the invention further relates to (compositions comprising any one of) the compound, salt thereof, crystal thereof, co-crystal comprising it, or polymorph, isomer or amorphous form of said compound for use as a medicament or for use in the manufacture of a medicament; such as for use in (a method of) treating of a cancer or for use in the manufacture of a medicament for treating a cancer.
  • said medicament is combined with chemotherapy treatment or a combined modality chemotherapy treatment.
  • said cancer treatment is a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • the drug moiety D of the compound C-OP-D is effective as cytotoxic, cytostatic, or anti-cancer drug in a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • the invention further relates to methods for synthesizing or producing any of the above compounds, said methods comprising the steps of: linking the drug D, the tetrapeptidic moiety OP, and the capping group C; wherein the linking of D, OP and C is resulting in the compound C-OP-D, and wherein the linking between drug D and tetrapeptidic moiety OP is direct or via a linker or spacing group and/or the linking between C and OP is direct, or is indirect via a linker or spacing group.
  • Any of the production or synthesis methods may further be comprising a step of purifying the compound C-OP-D and/or comprising a step of forming a salt, amorphous form, crystal or co-crystal of the compound C-OP-D.
  • the invention further envisages kits comprising a container comprising the compound, salt thereof crystal thereof, co-crystal comprising it, or polymorph, isomer or amorphous form of said compound or a composition comprising any one of the foregoing.
  • FIG. 1 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on colorectal cancer cells.
  • HCT-116 cells were seeded at a density of 10.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • FIG. 3 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on triple negative breast cancer cells.
  • MDA-MB-468 cells were seeded at a density of 10.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • FIG. 4 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on ovarian cancer cells.
  • A-B A2780 (endometrial adenocarcinoma) and
  • C-D A2780 Cis (cisplatin resistant variant of the same parental line) cells were seeded at a density of 10.000-12.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • FIG. 1 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on lung cancer cells.
  • A- B NCI-H1299 cells were seeded at a density of 7.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • A Potency of PhAc-NLGP-Dox, PhAc-VAGP-Dox, PhAc-IAGP-Dox and PhAc-LAGP-Dox.
  • A2058 cells were seeded at a density of 7.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • A Potency of PhAc-NLGP-Dox, PhAc-VAGP-Dox, PhAc-IAGP-Dox and PhAc-LAGP-Dox.
  • FIG. 7 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on prostate cancer cells.
  • DU145 cells were seeded at a density of 5.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • FIG. 8 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on pancreatic cancer cells.
  • MIA PaCa-2 cells were seeded at a density of 10.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • FIG. 9 Cytotoxicity of doxorubicin and doxorubicin-comprising prodrugs on normal cells.
  • A-B Immortalized human mammary epithelial (HME-1) and
  • C-D human umbilical vein endothelial cells (HUVEC) were seeded at a density of 10.000 cells/well and exposed to a l-in-5 serial dilution, starting from 100 pM doxorubicin-comprising prodrug or 10 pM doxorubicin (free drug) for 72 hrs.
  • W02014/102312 identified prodrugs comprising tetrapeptides ALGP (SEQ ID NO:11), KLGP (SEQ ID NO:12) or TSGP (SEQ ID NO:13), which are cleavable by LS174T tumor cell-conditioned medium were.
  • W02014/102312 clarified that other XXGP tetrapeptides (i.e. DLGP (SEQ. ID NO:14), AIGP (SEQ ID NO:15), or GPGP (SEQ ID NO:16)) included in a similar constellation in a prodrug are not cleaved by LS174T tumor cell-conditioned medium, thus indicating that the "XX" amino acids cannot be randomly chosen.
  • the prodrug compounds of WQ2014/102312 have the general structure C-OP-D (C: capping group; OP: tetrapeptide; D: drug).
  • C capping group
  • OP tetrapeptide
  • D drug
  • XXGP tetrapeptides were identified which, when included in a C-OP-D-type compound, were capable of releasing the drug D when incubated with a range of different cancer cells, and which exerted specific cytotoxicity to the cancer cells without killing normal cells.
  • compounds withheld in the current invention were only those displaying a selectivity index (SI) of at least 2 towards at least 2 out of the 9 tested cancer cell lines. Indeed, compounds with a selectivity index greater than 2, were described as having the potential for exerting an increased therapeutic window (Badisa et al. 2009, Anticancer Res 29:2993-2996).
  • the present invention describes new prodrug compounds of therapeutic agents with improved therapeutic properties, especially prodrugs comprising a therapeutic agent, in particular a therapeutic agent useful for treating a tumor or cancer.
  • prodrug in general refers to a compound that undergoes biotransformation before exhibiting pharmacological effects. Prodrugs can thus be viewed as drugs containing specific nontoxic protective groups present in a transient manner to alter or to eliminate undesirable properties in the parent molecule (from: Vert et al. 2012, Pure Appl Chem 84:377-410).
  • the protective groups can have one or more function such as increasing bioavailability, increasing solubility, increasing stability, avoiding or reducing premature release of the drug (thus avoiding or reducing toxicity), altering cell permeability, avoiding or reducing irritation in the subject to be treated with the drug, supporting administration of the drug to the targeted cells or organs in a subject, etc..
  • tetrapeptide-comprising compounds also termed C- OP-D compounds, C-OP-D prodrugs, or C-OP-D prodrug compounds, or, simply compounds (according to the invention) or prodrugs (according to the invention)
  • serendipity as being prodrugs displaying a favourable selectivity towards cancer cells (compared to healthy or non-cancer cells); the activation mechanism behind the release of the active drug moiety from these prodrugs currently remains unknown.
  • the compounds of the invention have the general structure C-OP-D, wherein:
  • C is a capping group
  • OP is a tetrapeptidic moiety selected from (the group consisting of)
  • D is a drug; a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph or a pharmaceutically acceptable isomer of said compound.
  • the compounds of the invention have the general structure C-OP-D, wherein: C is a capping group;
  • OP is a tetrapeptidic moiety selected from (the group consisting of)
  • AAGP (SEQ ID NO:4); AVGP (SEQ ID NO:5); MLGP (SEQ ID NO:6); NLGP (SEQ ID NO:7); IAGP (SEQ ID NO:8); LAGP (SEQ ID NO:9); and VAGP (SEQ ID NQ:10);
  • D is a drug; a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph or a pharmaceutically acceptable isomer of said compound.
  • the compounds of the invention have the general structure C-OP-D, wherein:
  • C is a capping group
  • OP is a tetrapeptidic moiety selected from (the group consisting of)
  • D is a drug; a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable crystal or co-crystal comprising said compound, or a pharmaceutically acceptable polymorph or a pharmaceutically acceptable isomer of said compound.
  • OP is the tetrapeptidic moiety AAGP (SEQ ID NO:4).
  • OP is the tetrapeptidic moiety AVGP (SEQ ID NO:5).
  • OP is the tetrapeptidic moiety MLGP (SEQ ID NO:6). In a further embodiment, OP is the tetrapeptidic moiety NLGP (SEQ ID NO:7). In a further embodiment, OP is the tetrapeptidic moiety IAGP (SEQ ID NO:8). In a further embodiment, OP is the tetrapeptidic moiety LAGP (SEQ ID NO:9); In a further embodiment, OP is the tetrapeptidic moiety VAGP (SEQ ID NQ:10).
  • tetrapeptide is a key determinant of the selectivity (determined e.g. as described in the Examples hereinafter) of the above prodrug compounds, this independent of which drug is incorporated in the prodrug compound.
  • Historical examples further corroborate this. For instance, Dubowchik et al. 1998 (Bioorg Med Chem Lett 8:3341-3346 and 3347-3352) and Walker et al. 2004 (Bioorg Med Chem Lett 14:4323-4327) demonstrated that once a suitable peptidic moiety has been identified, the drug D can be changed (demonstrated for doxorubicin, mitomycin C, and tallysomycin SlOb).
  • prodrug once a suitable peptidic moiety is identified, the drug D can be changed (demonstrated for doxorubicin and paclitaxel; Elsadek et al. 2010, ACS Med Chem Lett 1: 234-238, and Elsadek et al. 2010, Eur J Cancer 46:3434- 3444).
  • prodrugs can even be linked successfully to antibodies targeting a tumor-specific antigen (Dubowchik et al. 2002, Bioconjugate Chem 13:855-869; and Walker et al.
  • the tetrapeptidic moiety OP and the drug D in the general prodrug structure C-OP-D are directly linked (or coupled or bound) to each other, or, alternatively are linked (or coupled or bound) indirectly via a linker or spacing group.
  • the linkage should: (1) not or not significantly disturb the functionality of the tetrapeptidic moiety, i.e., should not or not significantly disturb the proteolytic scissability of OP and (2) should retain the blood stability of the compound. Determination of the functionality of a linker or spacing group in the prodrug can be tested (e.g. stability in mammalian serum, selective toxicity to cancerous cells).
  • a linker or spacing group (terms used interchangeably herein) can be present to create distance between the tetrapeptidic moiety and the drug moiety such as a spacer for mitigating steric hindrance in order to facilitate proteolytic or other enzymatic degradation of the tetrapeptidic moiety OP linked to the drug moiety D.
  • Such linker or spacing group can alternatively or additionaly be present to (further) increase the specificity of the prodrug compound, e.g. by providing an additional mechanism for activation of the prodrug compound or release of the drug moiety D from the C-OP-D compound.
  • linker or spacing group can further alternatively or additionally be present to enable chemical linkage between the tetrapeptidic moiety and the drug moiety, i.e. the end of the linker to be connected with the drug moiety can be designed in function of chemical coupling with a suitable group present in the chemical structure of the drug moiety.
  • a linker or spacing group may thus provide appropriate attachment chemistry between the different moieties of the C-OP-D compound (and thus providing flexibility to couple any possible drug moiety D and a tetrapeptidic moiety OP of the invention).
  • a linker or spacing group may further alternatively or additionaly be introduced to improve the synthetic process of making the C-OP-D conjugate (e.g., by pre-derivatizing the therapeutic agent or oligopeptide with the linker group before conjugation to enhance yield or specificity).
  • a linker or spacing group may yet further alternatively or additionaly be introduced to improve physical properties of the C-OP-D compound.
  • linker or spacing group may be purely self-immolative or selfeliminating by means of chemical degradation upon release of/from the tetrapeptidic moiety.
  • Self- immolation or self-elimination of a linker or spacing group may alternatively rely on further triggers such as esterase or phosphatase activity or may rely on a redox-sensitive, pH-sensitive, etc. triggering mechanism; in the current context such linkers are likewise termed self-immolative or self-eliminating linkers or spacing groups.
  • the linker between OP and D can for instance be a self-immolative or self-eliminating linker or spacing group. Upon proteolytic removal of the tetrapeptidic moiety OP, such linker is spontaneously decomposing to set free the drug moiety D.
  • the different types of self-eliminating linkers usually decompose via a spontaneous elimination or cyclization reaction.
  • a well-known and often used self- immolative linker is p-aminobenzyloxycarbamate (PABC; alternatively p-aminobenzyloxycarbonyl) which decomposes via 1,6-benzyl elimination; o-aminobenzyloxycarbonyl (OABC) decomposes via 1,4- benzyl elimination.
  • PABC p-aminobenzyloxycarbamate
  • OABC o-aminobenzyloxycarbonyl
  • Linkers such as PABC are able to connect either -OH, -COOH, - NH, or -SH groups of a drug D at the one hand to the carboxy-terminal group of a tetrapeptidic moiety OP at the other hand.
  • Substituted 3-carbamoyl-2-arylpropenal compounds are a further example of self-immolative linkers that decompose via elimination of carbamic acid; substitutions include a nitro-group, a halide (e.g. fluoride), and a methyl group (Rivault et al. 2004, Bioorg Med Chem 12:675).
  • Self-immolative disulfide-containing linkers are a newer group of such linkers (e.g.
  • Such self-immolative linkers can be multimerized (e.g. dimers, trimers,...) to form elongated self- immolative linkers.
  • Such linkers can also be multimerized in the form of dendrimers potentially carrying multiple drug D moieties (e.g. Amir et al. 2003, Angew Chem Int Ed 42:4494-4499; de Groot et al. 2003, Angew Chem Int Ed 42:4490-4494).
  • the linker between OP and D can for instance be an acid-labile linker.
  • acid-labile linkers are preferentially cleaved in the tumor environment.
  • Acid-labile linkers or spacers include acid-labile bonds such as carboxylic hydrazine bonds, cis-aconityl bonds, trityl bonds, acetal bonds and ketal bonds.
  • Polymeric molecules in which the monomers are each linked to each other by an acid-labile bond are other examples of acid-labile linkers (see e.g. Figure 10 and Table 5 of Kratz et al. 2008, ChemMedChem 3:20-53).
  • the linker between OP and D can for instance be a self-immolative or self-eliminating linker or spacing group wherein the self-immolation or self-elimination is occurring selectively under hypoxic/low oxygen conditions.
  • Many tumors or cancers, in particular solid tumors or cancers, are characterized by the presence of hypoxic regions (e.g. Li et al. 2018, Angew Chem Int Ed Engl 57:11522-11531).
  • Aromatic nitro or azido groups can be applied in this setting and reduction (in hypoxic or low oxygen areas) of these compounds starts their decomposition via 1,6- or 1,8-elimination.
  • Analogues of nitroimidazoles, N-oxides and nitrobenzyl carbamates can be applied (e.g. imidazolylmethyl carbamates: Hay et al. 2000, Tetrahedron 56:645; e.g. nitrobenzyloxycarbonyl groups: Shyam et al.
  • Self-elimination of a linker between OP and D can also be based on an intramolecular cyclization or lactonization reaction, such as the trimethyl lock lactonization reaction (Greenwald et al. 2000, J Med Chem 43:475-487).
  • Such systems include, without limitation, the (alkylamino)-ethyl carbamate and [(alkylamino)ethyl]glycyl ester systems; the N-(substituted 2-hydroxyphenyl) carbamate and N- (substituted 2-hydroxypropyl) carbamate systems; and systems based on o-hydroxylphenylpropionic acid and its derivatives.
  • the linker between OP and D can for instance be redox-sensitive linkers susceptible to reducing conditions (such as quinones).
  • the linker between OP and D can for instance be a hydrophilic stopper such as a glycosylated tetra(ethylene glycol) which, upon deglycosylation (after proteolytic release of the tetrapeptidic moiety OP), spontaneous decomposes and releases the drug D (e.g. Fernandes et al. 2012, Chem Commun 48:2083-2085).
  • a hydrophilic stopper such as a glycosylated tetra(ethylene glycol) which, upon deglycosylation (after proteolytic release of the tetrapeptidic moiety OP), spontaneous decomposes and releases the drug D (e.g. Fernandes et al. 2012, Chem Commun 48:2083-2085).
  • linker or spacer groups examples include aminocaproic acid, a hydrazide group, en ester group, an ether group, a sulphydryl group, ethylenediamine (or longer -CH2- chains), aminoalcohol, and ortho-phenylenediamine (1,2-diaminobenzene).
  • the linker or spacer is not a self-immolative linker.
  • Such non-self- immolative linker may still be cleavable by an enzyme present outside or inside a target cell.
  • the linker or spacer between the drug D and the tetrapeptide moiety OP is not comprising a proteinaceous moiety such as an L-amino acid or a derivative of an L-amino acid. In a further embodiment, said linker or spacer is not comprising a D-amino acid or a derivative of a D- amino acid. In a further embodiment, said linker or spacer is not comprising a non-natural amino acid.
  • the general compound structure C-OP-D described hereinabove may be complexed with a macrocyclic moiety, e.g. a self-eliminating or self-immolative macrocyclic moiety.
  • the self-elimination process may be a pure self-elimination process or one that is started by a further trigger (see above).
  • the tetrapeptidic axle of a compound C-OP-D could further be protected by means of a macrocycle itself designed to be self-immolative or self-opening, wherein the trigger for self-immolation or selfopening could be action of an enzyme such as beta-galactosidase or beta-glucuronidase.
  • a macrocycle is hereinafter furher termed "macrocyclic moiety". Expression of beta-galactosidase is increased in many tumors compared to normal tissues (e.g. Chen et al. 2018, Anal Chim Acta 1033:193- 198) and glucuronide prodrugs are a further class of prodrugs (e.g. Tranoy-Opalinski et al.
  • Trapping the tetrapeptidic moiety OP of the compound of the invention in a macrocycle preferentially opening in the vicinity of tumor cells adds an additional layer of selectivity to a compound of the invention.
  • One example of such macrocycle is a rotaxane or pseudo-rotaxane, and protection against self-opening could be through e.g. linkage with a glycoside such as a galactoside.
  • the glycoside moiety can be linked to the macrocycle through a self-immolative linker.
  • An example of such compound capable of protecting the tetrapeptidic axle of the compound of the invention is described by e.g. Barat et al.
  • a direct linkage between the capping group C and the tetrapeptidic moiety OP may be direct, e.g. via the N-terminal aminogroup of the tetrapeptidic moiety OP, or via a side chain of one of the amino acids of the tetrapeptidic moiety OP.
  • said linkage may be indirect, e.g. by introducing a linker or spacer group between the tetrapeptidic moiety OP and the capping group C.
  • the linkage should: (1) not or not significantly disturb the functionality of the tetrapeptidic moiety, i.e., should not or not significantly disturb the proteolytic scissability of OP and (2) should retain the blood stability of the compound. Determination of the functionality of a linker or spacing group in the prodrug compound can be tested (e.g. stability in mammalian serum, selective toxicity to cancerous cells, etc.). Possible reasons for including a linker or spacing group between the capping group C and the tetrapeptidic moiety OP are the same as those listed hereinabove relating to the linker or spacing group between the tetrapeptidic moiety OP and the drug moiety D.
  • the linker or spacer between the capping group C and the tetrapeptide moiety OP is not comprising a proteinaceous moiety such as an L-amino acid or a derivative of an L- amino acid.
  • said linker or spacer is not comprising a D-amino acid or a derivative of a D-amino acid.
  • said linker or spacer is not comprising a nonnatural amino acid.
  • a protecting or capping moiety C adds to the solubility and/or stability of the prodrug compound (e.g. in mammalian blood or serum) and/or adds to the prevention of internalization of the prodrug compound into a cell such as a target cell.
  • Such protecting or capping moieties include non-natural amino acids, p-alanyl or succinyl groups (e.g. WO96/05863, US 5,962,216).
  • Further stabilizing, protecting or capping moieties include diglycolic acid, maleic acid, pyroglutamic acid, glutaric acid, (e.g., WOOO/33888), a carboxylic acid, adipic acid, phthalic acid, fumaric acid, naphthalene dicarboxylic acid, 1,8-naphtyldicarboxylic acid, aconitic acid, carboxycinnamic acid, triazole dicarboxylic acid, butane disulfonic acid, polyethylene glycol (PEG) or an analog thereof (e.g., WOOl/95945), acetic acid, 1- or 2-naphthylcarboxylic acid, gluconic acid, 4- carboxyphenyl boronic acid, polyethylene glycolic acid, nipecotic acid, and isonipecotic acid (e.g., W002/00263, W002/100353), succinylated polyethylene glycol (e.g
  • W02008/120098 A new type of protecting or capping moiety was introduced in W02008/120098, being a 1,2, 3, 4 cyclobutanetetracarboxylic acid.
  • the protecting or capping moiety in W002/07770 may be polyglutamic acid, carboxylated dextranes, carboxylated polyethylene glycol or a polymer based on hydroxyprolyl-methacrylamide or N-(2-hydroxyprolyl)methacryloylamide.
  • Other capping groups include epsilon-maleimidocaproyl (Elsadek et al. 2010, EurJ Cancer 46:3434-3444), benzyloxycarbonyl (Dubowchik et al. 1998, Bioorg Med Chem Lett 8:3341-3346), and succinyl and phosphonoacetyl (e.g. WO 2014/102312).
  • polyethylene glycol group(s) may be linked, coupled or bound to an amino acid, such as the N-terminal amino acid, of the tetrapeptidic moiety OP.
  • pegylation may be introduced in order to increase the half-life of a compound C-OP-D in circulation after administration to a mammal and/or to increase solubility of a compound C-OP-D.
  • Addition of (a) polyethylene glycol group(s)/pegylation could alternatively or additionally play the role of a capping agent.
  • the drug moiety D or therapeutic agent conjugated to the tetrapeptidic moiety OP of the invention may be useful for treatment of cancer (e.g. by exerting cytostatic, cytotoxic, anti-cancer or antiangiogenic activity; e.g. as adjuvant therapy, as part of a treatment regimen), inflammatory disease, or some other medical condition.
  • the drug moiety D or therapeutic agent D may be any drug or therapeutic agent capable of entering a target cell (passively or by any uptake mechanism).
  • the therapeutic agent may be selected from a number of classes of compounds including, alkylating agents, antiproliferative agents, tubulin binding agents, vinca alkaloids, enediynes, podophyllotoxins or podophyllotoxin derivatives, the pteridine family of drugs, taxanes, anthracyclines (and oxazolino anthracyclines, Rogalska et al. 2018n PLoS One 13:e0201296), dolastatins or their analogues (such as auristatins), topoisomerase inhibitors, platinum-coordination-complex chemotherapeutic agents, and maytansinoids.
  • alkylating agents including, alkylating agents, antiproliferative agents, tubulin binding agents, vinca alkaloids, enediynes, podophyllotoxins or podophyllotoxin derivatives, the pteridine family of drugs, taxanes, anthracyclines (and oxazol
  • said drug moiety D or therapeutic agent may be one of the following compounds, or a derivative or analog thereof: doxorubicin and analogues [such as N-(5,5-diacetoxypent-l- yl)doxorubicin: Farquhar et al. 1998, J Med Chem 41:965-972; epirubicin (4'-epidoxorubicin), 4'- deoxydoxorubicin (esorubicin), 4'-iodo-4'-deoxydoxorubicin, and 4'-O-methyldoxorubicin: Arcamone et al. 1987, Cancer Treatment Rev 14:159-161 & Giuliani et al.
  • doxorubicin and analogues such as N-(5,5-diacetoxypent-l- yl)doxorubicin: Farquhar et al. 1998, J Med Chem 41:965-972; epirubicin (4'-epidoxorubi
  • DOX- F-PYR pyrrolidine analog of DOX
  • DOX-F-PIP piperidine analog of DOX
  • DOX-F-MOR morpholine analog of DOX
  • DOX-F-PAZ N-methylpiperazine analog of DOX
  • DOX-F-HEX hexamehtyleneimine analog of DOX
  • oxazolinodoxorubicin (3'deamino-3'-N, 4'-O-methylidenodoxorubicin, O-DOX): Denel- Bobrowska et al.
  • daunorubicin or daunomycin
  • analogues thereof such as idarubicin (4'-demethoxydaunorubicin): Arcamone et al. 1987, Cancer Treatment Rev 14:159-161; 4'-epidaunorubicin; analogues with a simplified core structure bound to the monosaccharide daunosamine, acosamine, or 4-amino-2,3,6-trideoxy-L-threo-hexopyranose: see compounds 8-13 in Fan et al.
  • auristatins such as auristatins, e.g. auristatin E, auristatin-PHE, monomethyl auristatin D, monomethyl auristatin E, monomethyl auristatin F; see e.g. Maderna et al.
  • Other therapeutic agents or drugs include: vindesine, vinorelbine, 10-deacetyltaxol, 7-epi-taxol, baccatin III, 7-xylosyltaxol, isotaxel, ifosfamide, chloroaminophene, procarbazine, chlorambucil, thiophosphoramide, busulfan, dacarbazine (DTIC), geldanamycin, nitroso ureas, estramustine, BCNU, CCNU, fotemustine, streptonigrin, oxaliplatin, methotrexate, aminopterin, raltitrexed, gemcitabine, cladribine, clofarabine, pentostatin, hydroxyureas, irinotecan, topotecan, 9- dimethylaminomethyl- hydroxy-camptothecin hydrochloride, teniposide, amsacrine; mitoxantrone; L
  • analogue of a compound generally refers to a structural analogue or chemical analogue of that compound. Analogues include, but are not limited to isomers.
  • derivative of a compound refers to a compound that is structurally similar to and retains sufficient functional attributes of the original compound.
  • the derivative may be structurally similar because one or more atoms are lacking, are substituted, are in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, adding a hydroxyl group, replacing an oxygen atom with a sulfur atom, or replacing an amino group with a hydroxyl group, oxidizing a hydroxyl group to a carbonyl group, reducing a carbonyl group to a hydroxyl group, and reducing a carbon-to-carbon double bond to an alkyl group or oxidizing a carbon- to-carbon single bond to a double bond compared to the original compound.
  • a derivative optionally has one or more, the same or different, substitutions.
  • Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated by reference.
  • “Pharmaceutically acceptable”, as used herein, such as in the context of salts, crystals, co-crystals, polymorphs and isomers, means those salts of C-OP-D compounds of the invention that are safe and effective for the intended medical use.
  • any of such salts, crystals, co-crystals, polymorphs and isomers that possess the desired biological activity are safe and effective for the intended medical use.
  • Salts Any of numerous compounds that result from replacement of part or all of an acidic or basic group present in a drug moiety D or compound C-OP-D of the invention. Suitable salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • Suitable salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • Co-crystals are crystalline materials composed of two or more different molecules, typically an API or drug and co-crystal formers ("coformers"), in the same crystal lattice.
  • Pharmaceutical co-crystals have opened up opportunities for engineering solid-state forms beyond conventional solid-state forms of an API or drug, such as salts and polymorphs.
  • Co-crystals are readily distinguished from salts because unlike salts, their components are in a neutral state and interact nonionically.
  • co-crystals differ from polymorphs, which are defined as including only single-component crystalline forms that have different arrangements or conformations of the molecules in the crystal lattice, amorphous forms, and multicomponent phases such as solvate and hydrate forms.
  • co-crystals are more similar to solvates, in that both contain more than one component in the lattice. From a physical chemistry perspective, co-crystals can be viewed as a special case of solvates and hydrates, wherein the second component, the coformer, is nonvolatile. Therefore, co-crystals are classified as a special case of solvates in which the second component is nonvolatile.
  • stereoisomeric molecules or stereoisomers, contain the same atoms linked together in the same sequence (same molecular formula), but having different three-dimensional organizations or configurations.
  • Optical isomers also sometimes referred to as enantiomers, are molecules which are non-superposable mirror images of each other. Depending on the optical activity, enantiomers are often described as left- or right-handed, and each member of the pair is referred to as enantiomorph
  • each enantiomorph being a molecule of one chirality.
  • Mixtures of equal parts of two enantiomorphs are often referred to as racemic mixtures.
  • Compounds comprising within the limits of detection only one enantiomorph are referred to as enantiopure compounds.
  • Optical isomers can occur when molecules comprise one or more chiral centers.
  • Geometric isomers usually refer to cis-trans isomers wherein rotation around a chemical bond is impossible. Cis-trans isomers often are found in molecules with double or triple bonds.
  • Structural isomers contain the same atoms (same molecular formula), but linked together in a different sequence.
  • a further aspect of the invention relates to a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) as disclosed herein for use as a medicament or for use in the manufacture of a medicament.
  • the medicament is for use in e.g. the treatment of a cancer.
  • compositions comprising a salt of a compound C-OP-D, a crystal or co-crystal comprising a compound C-OP-D, a polymorph or amorphous form of a compound C-OP-D, or an isomer of a compound C-OP-D.
  • compositions comprising a pharmaceutically acceptable salt of a compound C-OP-D, a pharmaceutically acceptable crystal or co-crystal comprising a compound C-OP-D, a pharmaceutically acceptable polymorph of the compound C-OP-D, a pharmaceutically acceptable amporphous form of the compound C-OP-D, or a pharmaceutically acceptable isomer of a compound C-OP-D.
  • such composition is a pharmaceutically acceptable composition and is further comprising at least one of a pharmaceutically acceptable solvent, diluent, or carrier.
  • a further aspect of the invention relates to compositions comprising a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) as disclosed herein.
  • any of the above compositions can be used as medicament, or are for use in the manufacture of a medicament; such medicament is e.g. for use in the treatment of a cancer.
  • any of the above compositions is a pharmaceutically acceptable composition and is further comprising at least one of a pharmaceutically acceptable solvent, diluent, or carrier.
  • a composition of the invention thus can comprise besides the compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) any one of a suitable solvent (capable of solubilizing the prodrug compound to the desired extent), diluent (capable of diluting concentrated prodrug compound to the desired extent) or carrier (any compound capable of absorbing, adhering or incorporating the prodrug compound, and of subsequently releasing at any rate the prodrug compound in the extracellular compartment of the subject's body).
  • Said composition may alternatively comprise multiple (i.e.
  • prodrug compounds or salt, crystal, polymporph, or amorphous form isomer thereof, or co-crystal comprising it, or any combination thereof (e.g. prodrug compound 1 + its salt, prodrug compound 1 + prodrug compound 2, prodrug compound 1 + its salt + prodrug compound 2, etc.).
  • said solvent, diluent or carrier is pharmaceutically acceptable, i.e., is acceptable to be administered to a subject to be treated with the composition of the invention. Aiding in formulating a pharmaceutically acceptable composition is e.g. any Pharmacopeia book.
  • composition may be formulated such that it is suitable for any way of administration including intra-cranial, intra-spinal, enteral, parenteral, intra-organ, intra-tumoral, intra-thecal, epidural etc. administration.
  • the regimen by which the prodrug compound is administered may vary, e.g. depending on its pharmacokinetic characteristics, depending on the formulation, depending on the overall physical condition of a subject to be treated and e.g. depending on the judgment of the treating physician.
  • the compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) of the invention, or a composition comprising it, is particularly suitable for treating a disease that is treatable by the released drug.
  • a disease that is treatable by the released drug.
  • cancer includes e.g.
  • breast cancers soft tissue sarcoma, colorectal cancers, liver cancers, lung cancers such as small cell, non-small cell, bronchic cancers, prostate cancers, renal cancer, esophageal cancer, ovarian cancers, brain cancers, and pancreatic cancers, colon cancers, head and neck cancers, stomach cancers, bladder cancers, non-Hodgkin's lymphomas, leukaemias, neuroblastomas, glioblastomas, mesenchymal-like adenocarcinomas, basal-like adenocarcinomas, endometrioid adenocarcinomas, (metastatic) non-small cell lung carcinomas, (metastatic) melanomas, mucoepithelial pulmonary carcinomas, colon carcinomas, colon adenocarcinomas, prostate carcinomas, pancreatic ductal carcinomas.
  • lung cancers such as small cell, non-small cell, bronchic cancers, prostate cancers, renal cancer, e
  • the subject to be treated with the compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) of the invention can be any mammal in need of such treatment but is in particular a human.
  • the treatment can result in regression of the disease [e.g. in terms of decreasing (primary) tumor volume or (primary) tumor mass and/or in terms of decreasing or inhibiting metastasis (e.g. number and/or growth of metastases), in decreased progression of the disease compared to expected disease progression, or in stabilization of the disease, i.e. neither regression nor progression of the disease. All these are favorable outcomes of the treatment.
  • the effective amounts of said compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), or of said composition is not causing severe leukopenia or cardiac toxicity/cardiotoxicity at therapeutic dosage.
  • severe human leukopenia is WHO-criteria-defined grade 3- (1000-1900 leukocytes/mL) or grade 4-leukopenia (less than 1000 leukocytes/mL).
  • Treatment refers to any rate of reduction, delay or retardation of the progress of the disease or disorder, or a single symptom thereof, compared to the progress or expected progress of the disease or disorder, or singe symptom thereof, when left untreated. This implies that a therapeutic modality on its own may not result in a complete or partial response (or may even not result in any response), but may, in particular when combined with other therapeutic modalities, contribute to a complete or partial response (e.g. by rendering the disease or disorder more sensitive to therapy). More desirable, the treatment results in no/zero progress of the disease or disorder, or singe symptom thereof (i.e.
  • Treatment/treating also refers to achieving a significant amelioration of one or more clinical symptoms associated with a disease or disorder, or of any single symptom thereof. Depending on the situation, the significant amelioration may be scored quantitatively or qualitatively. Qualitative criteria may e.g. be patient well-being.
  • the significant amelioration is typically a 10% or more, a 20% or more, a 25% or more, a 30% or more, a 40% or more, a 50% or more, a 60% or more, a 70% or more, a 75% or more, a 80% or more, a 95% or more, or a 100% improvement over the situation prior to treatment.
  • the time-frame over which the improvement is evaluated will depend on the type of criteria/disease observed and can be determined by the person skilled in the art.
  • a “therapeutically effective amount” refers to an amount of a therapeutic agent to treat or prevent a disease, disorder, or unwanted condition in a subject.
  • the term “effective amount” refers to the dosing regimen of the agent or composition comprising the agent (e.g. medicament or pharmaceutical composition).
  • the effective amount will generally depend on and/or will need adjustment to the mode of contacting or administration.
  • the effective amount of the agent or composition comprising the agent is the amount required to obtain the desired clinical outcome or therapeutic effect without causing significant or unnecessary toxic effects (often expressed as maximum tolerable dose, MTD).
  • MTD maximum tolerable dose
  • the agent or composition comprising the agent may be administered as a single dose or in multiple doses (see explanation on single administrations), such as to obtain or maintain the effective amount over the desired time span/treatment duration.
  • the effective amount may further vary depending on the severity of the condition that needs to be treated; this may depend on the overall health and physical condition of the mammal or patient and usually the treating doctor's or physician's assessment will be required to establish what is the effective amount.
  • the effective amount may further be obtained by a combination of different types of contacting or administration.
  • administering means any mode of contacting that results in interaction between an agent (e.g. a therapeutic compound) or composition comprising the agent (such as a medicament or pharmaceutical composition) and an object (e.g. cell, tissue, organ, body lumen) with which said agent or composition is contacted.
  • agent e.g. a therapeutic compound
  • object e.g. cell, tissue, organ, body lumen
  • parenteral administration intravenous, intramuscular, subcutaneous
  • intrathecal administration intracerebral administration, epidural administration, intracardial administration, intraosseous administration, intraperitoneal administration, (mini)pump-controlled administration, administration in the vicinity of a cancer or tumor, administration via a cathether or a peripherally inserted central catheter or percutaneous indwelling central catheter, and includes e.g. bolus administration.
  • the interaction between the agent or composition and the object can occur starting immediately or nearly immediately with the administration of the agent or composition, can occur over an extended time period (starting immediately or nearly immediately with the administration of the agent or composition), or can be delayed relative to the time of administration of the agent or composition. More specifically the "contacting" results in delivering an effective amount of the agent or composition comprising the agent to the object.
  • a single administration of a pharmacologic compound in general leads to a transient effect due to its gradual removal from the cell, organ and/or body and is reflected in the pharmacokinetic/-dynamic behavior of the compound.
  • two or more (multiple) administrations of the pharmacologic compound may thus be required.
  • “Combination” or “combination in any way” or “combination in any appropriate way” as referred to herein is meant to refer to any sequence of administration of two (or more) therapeutic modalities, i.e. the administration of the two (or more) therapeutic modalities can occur concurrently or separated from each other for any amount of time; and/or "combination", “combination in any way” or “combination in any appropriate way” as referred to herein can refer to the combined or separate formulation of the two (or more) therapeutic modalities, i.e. the two (or more) therapeutic modalities can be individually provided in separate vials or (other suitable) containers, or can be provided combined in the same vial or (other suitable) container.
  • the two (or more) therapeutic modalities can each be provided in the same vial/container chamber of a single-chamber vial/container or in the same vial/container chamber of a multi-chamber vial/container; or can each be provided in a separate vial/container chamber of a multichamber vial/container.
  • the therapeutic modalities of the current invention are a compound of the formula C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) and an immune checkpoint inhibitor.
  • Combinations of a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) as disclosed herein with a chemotherapeutic agent and/or with one or more alkylating antineoplastic agent(s) and/or one or more anti-metabolite(s) and/or one or more anti-microtubule agent(s) and/or one or more topoisomerase inhibitor(s) and/or one or more cytotoxic antibiotic(s) and/or one or more (biological) anticancer agent(s) (such as antibodies) and/or with one or more immunotherapeutic agents are one aspect of the invention.
  • a compound C-OP-D or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it
  • this can be in a combined modality chemotherapy, i.e. the use of the anticancer compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) with other cancer treatments, such as radiation therapy (whether by direct irradiation or via administering an isotope-labeled antibody or antibody fragment) or surgery.
  • This can also be in combination chemotherapy, i.e.
  • combination chemotherapy treating a patient with a number of different drugs wherein the drugs preferably differ in their mechanism of action and in their side effects.
  • the different drugs can be administered simultaneously (but not necessarily combined in a single composition) or separated in any order one relative to another.
  • An advantage of combination chemotherapy is the minimization of the chance of the development of resistance to any one agent.
  • a further advantage may be that the individual drugs can each be used at a lower dose, thereby reducing overall toxicity.
  • a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention, or a composition comprising such compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), can thus be used (in a method) for manufacture of a medicament; such as for manufacture of a medicament for treatment of a disease (e.g. cancer), as monotherapy, or as part of a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • a disease e.g. cancer
  • a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention, or a composition comprising such compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), can thus be used (in a method) for treatment of a disease (e.g. cancer), as monotherapy, or as part of a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • a disease e.g. cancer
  • the compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), or a composition comprising it, is admininstered to a subject in need, therewith treating the disease.
  • a therapeutically effective dose or therapeuctically effective dose regimen of a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), or of a composition comprising it is administered to the subject in need, therwith treating the disease.
  • a subject in need in general is a subject, such as a mammal, having, suffering from, or diagnosed to have the disease.
  • an anticancer compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention can be combined with one or more alkylating antineoplastic agent(s) and/or one or more anti-metabolite(s) and/or one or more anti-microtubule agent(s) and/or one or more topoisomerase inhibitor(s) and/or one or more cytotoxic antibiotic(s) and/or one or more (biological) anticancer agent(s) (such as antibodies).
  • one or more of these can in one embodiment be included in a prodrug compound(s) (or a salt thereof) according to the present invention.
  • the prodrug compound(s) according to the present invention are not combined with a free drug D when D is present in said prodrug compound(s).
  • the prodrug compound(s) according to the present invention can be combined with one or more alkylating antineoplastic agent(s) different from D and/or one or more anti-metabolite(s) different from D and/or one or more anti-microtubule agent(s) different from D and/or one or more topoisomerase inhibitor(s) different from D and/or one or more cytotoxic antibiotic(s) different from D, wherein D is part of the prodrug compound C-OP-D as disclosed herein.
  • Immunotherapy is a promising new area of cancer therapeutics and several immunotherapies are being evaluated preclinically as well as in clinical trials and have demonstrated promising activity (Callahan et al. 2013, J Leukoc Biol 94:41-53; Page et al. 2014, Annu Rev Med 65:185-202).
  • chemotherapies can achieve higher rates of disease control by impinging on distinct elements of tumor biology to obtain synergistic antitumor effects. It is now accepted that certain chemotherapies can increase tumor immunity by inducing immunogenic cell death and by promoting escape in cancer immunoediting.
  • Immune checkpoints antagonists or inhibitors as referred to herein include the cell surface protein cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and their respective ligands.
  • CTLA-4 binds to its co-receptor B7-1 (CD80) or B7-2 (CD86); PD-1 binds to its ligands PD-L1 (B7-H10) and PD-L2 (B7-DC).
  • immune checkpoint inhibitors include the adenosine A2A receptor (AZAR), B7-H3 (or CD276), B7-H4 (or VTCN1), BTLA (or CD272), IDO (indoleamine 2,3-dioxygenase), KIR (killercell immunoglobulin-like receptor), LAG3 (lymphocyte activation gene-3), NOX2 (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform 2), TIM3 (T-cell immunoglobulin domain and mucin domain 3), VISTA (V-domain Ig suppressor of T cell activation), SIGLEC7 (sialic acid-binding immunoglobulin-type lectin 7, or CD328) and SIGLEC9 (sialic acid-binding immunoglobulin-type lectin 9, or CD329).
  • the immune checkpoint antagonists or inhibitors are selected for inclusion in a combination or combination therapy (a combination or combination
  • any compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention capable of inducing immunogenic cell death can be combined with an immunotherapeutic agent.
  • Drug moieties D known to induce immunogenic cell death include bleomycin, bortezomib, cyclophosphamide, doxorubicin, epirubicin, idarubicin, mafosfamide, mitoxantrone, oxaliplatin, and patupilone (Bezu et al. 2015, Front Immunol 6:187).
  • the drug doxorubicin (also known under trade names such as Adriamycin or Rubex) is commonly used to treat multiple types of cancers such as some leukemias and Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others. Doxorubicin is further used in different combination therapies.
  • Doxorubicin-containing therapies include AC or CA (Adriamycin, cyclophosphamide), TAC (Taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP (bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, prednisone), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisolone), FAC or CAF (5-fluorouracil, Adriamycin, cyclophosphamide), MVAC (methothrexate, vincristine, adriamycin, cisplatin), CAV (cyclophosphamide, doxorubicin, vincristine) and CAVE (CAV, etoposide), CVAD (cyclophosphamide,
  • combination chemotherapies such as BEP (Bleomycin, etoposide, platinum agent (cisplatin (Platinol))), CAPOX or XELOX (capecitabine, oxaliplatin), CBV (cyclophosphamide, carmustine, etoposide), FOLFIRI (fluorouracil, leucovorin, irinotecan), FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin), FOLFOX (fluorouracil, leucovorin, oxaliplatin), EC (epirubicin, cyclophosphamide), ICE (ifosfamide, carboplatin, etoposide (VP-16)) and IFL (irinotecan, leucovorin, fluorouracil).
  • BEP Boleomycin, etoposide, platinum agent (cisplatin (Platinol)
  • doxorubicin Combination of doxorubicin with sirolimus (rapamycin) has been disclosed by Wendel et al. 2004 (Nature 428, 332-337) in treatment of Akt-positive lymphomas in mice.
  • doxorubicin could be substituted by a compound C-OP-D (or salt, crystal, polymporph or isomer thereof, or co-crystal comprising it) as disclosed herein and wherein D is doxorubicin.
  • combination therapies including an anticancer compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention (whether alone or already part of a combination chemotherapy or of a combined modality therapy) and compounds other than cytostatics.
  • Such other compounds include any compound approved for treating cancer or being developed for treating cancer.
  • such other compounds include monoclonal antibodies such as alemtuzumab (chronic lymphocytic leukemia), bevacizumab (colorectal cancer), cetuximab (colorectal cancer, head and neck cancer), denosumab (solid tumor's bony metastases), gemtuzumab (acute myelogenous leukemia), ipilimumab (melanoma), ofatumumab (chronic lymphocytic leukemia), panitumumab (colorectal cancer), rituximab (Non-Hodgkin lymphoma), tositumomab (Non-Hodgkin lymphoma) and trastuzumab (breast cancer).
  • monoclonal antibodies such as alemtuzumab (chronic lymphocytic leukemia), bevacizumab (colorectal cancer), cetuximab (colorectal cancer, head and neck cancer), denosumab (solid
  • antibodies include for instance abagovomab (ovarian cancer), adecatumumab (prostate and breast cancer), afutuzumab (lymphoma), amatuximab, apolizumab (hematological cancers), blinatumomab, cixutumumab (solid tumors), dacetuzumab (hematologic cancers), elotuzumab (multiple myeloma), farletuzumab (ovarian cancer), intetumumab (solid tumors), matuzumab (colorectal, lung and stomach cancer), onartuzumab, parsatuzumab, pritumumab (brain cancer), tremelimumab, ublituximab, veltuzumab (non-Hodgkin's lymphoma), votumumab (colorectal tumors), zatuximab and anti-placental growth factor antibodies such as described
  • combination therapies include for instance CHOP-R (CHOP (see above)+ rituximab), ICE-R (ICE (see above) + rituximab), R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone) and TCH (Paclitaxel (Taxol), carboplatin, trastuzumab).
  • alkylating antineoplastic agents include nitrogen mustards (for example mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan), nitrosoureas (for example N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine and streptozotocin), tetrazines (for example dacarbazine, mitozolomide and temozolomide), aziridines (for example thiotepa, mytomycin and diaziquone (AZQ)), cisplatins and derivatives (for example cisplatin, carboplatin and oxaliplatin), and non-classical alkylating agents (for example procarbazine and hexamethylmelamine)
  • nitrogen mustards for example mechlorethamine, cyclophosphamide, melphalan
  • Subtypes of the anti-metabolites include the anti-folates (for example methotrexate and pemetrexed), fluoropyrimidines (for example fluorouracil, capecitabine and tegafur/uracil), deoxynucleoside analogues (for example cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin) and thiopurines (for example thioguanine and mercaptopurine).
  • fluoropyrimidines for example fluorouracil, capecitabine and tegafur/uracil
  • deoxynucleoside analogues for example cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin
  • thiopurines for example thioguanine and
  • Anti-microtubule agents include the vinca alkaloid subtypes (for example vincristine, vinblastine, vinorelbine, vindesine and vinflunine) and taxane subtypes (for example paclitaxel and docetaxel).
  • Other anti-microtubule agents include podophyllotoxin.
  • Topoisomerase inhibitors include topoisomerase I inhibitors (for example irinotecan, topotecan, camptothecin, exatecan, and SN-38 which is the active metabolite of irinotecan) and topoisomerase II inhibitors (for example etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone, and aclarubicin).
  • topoisomerase I inhibitors for example irinotecan, topotecan, camptothecin, exatecan, and SN-38 which is the active metabolite of irinotecan
  • topoisomerase II inhibitors for example etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone, and aclarubicin.
  • Cytotoxic drugs further include anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin and mitoxantrone) and other drugs including actinomycin, bleomycin, plicamycin and mitomycin.
  • anthracyclines doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin and mitoxantrone
  • other drugs including actinomycin, bleomycin, plicamycin and mitomycin.
  • CDK4/6 inhibitors such as palbociclib (PD-0332991), ribociclib, or abemaciclib.
  • PARP poly(ADP-ribose) polymerases
  • Any anticancer compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention can (whether alone or already part of a combination chemotherapy or of a combined modality therapy) further be included in an antibody- directed enzyme prodrug therapy (ADEPT), which includes the application of cancer-associated monoclonal antibodies, which are linked, to a drug-activating enzyme. Subsequent systemic administration of a non-toxic agent results in its conversion to a toxic drug, and resulting in a cytotoxic effect which can be targeted at malignant cells (Bagshawe et al. (1995) Tumor Targeting 1, 17-29.)
  • ADPT antibody- directed enzyme prodrug therapy
  • any anticancer compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention can (whether alone or already part of a combination chemotherapy or of a combined modality therapy) be combined with one or more agent(s) capable of reversing (multi)drug resistance ((M)DR reverser(s) or (M)DR reversing agent(s)) that can occur during chemotherapy.
  • agents include for example loperamide (Zhou et al. 2011, Cancer Invest 30, 119-125).
  • Another such combination includes loading the prodrug compound in nanoparticles such as iron oxide nanoparticles (Kievit et al.
  • doxorubicin HCL liposomes also known under the trade names Doxil, Caelyx or Myocet
  • daunorubicin known under the trade name DaunoXome
  • paclitaxel Garcion et al. 2006, Mol Cancer Ther 5, 1710-1722.
  • a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention, or a composition comprising such compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), can thus be used for manufacturing a medicament; such as a medicament for treating a disease (e.g. cancer), as monotherapy, or as part of a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • a disease e.g. cancer
  • a compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention, or a composition comprising such compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it), can thus be used (in a method) fortreatment of a disease (e.g. cancer), as monotherapy, or as part of a combination chemotherapy treatment or a combined modality chemotherapy treatment. Any of such treatments can further be combined with a treatment including a drug resistance reverting agent.
  • a compound C-OP-D (or salt, crystal, polymporph, isomer, or amorphous form thereof, or co-crystal comprising it) according to the invention, or a composition comprising such compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) is applied in a combination chemotherapy treatment or a combined modality chemotherapy treatment and the drug moiety D is effective or therapeutically effective as cytotoxic, cytostatic, or anti-cancer drug in a combination chemotherapy treatment or a combined modality chemotherapy treatment.
  • the invention relates to methods for synthesizing or producing a compound C-OP- D.
  • a method for producing a compound C-OP-D is a method comprising the steps of: linking the drug D, the tetrapeptidic moiety OP, and the capping group C; wherein the linking of D, OP and C is resulting in the compound C-OP-D, and wherein the linking between drug D and tetrapeptidic moiety OP and/or between capping group C and tetrapeptidic moiety OP is direct or via a linker or spacing group.
  • such method for synthesizing or producing a compound C-OP-D is a method wherein: the drug D is linked to the capped oligopeptide moiety complex C-OP, resulting in the compound C-OP-D; or wherein the drug D is linked to the tetrapeptidic moiety OP and the capping group C is linked to the tetrapeptidic moiety-drug complex OP-D, resulting in the compound C-OP-D; or wherein the drug D is linked to an intermediate of the tetrapeptidic moiety OP, the intermediate of the tetrapeptidic moiety is extended, and the capping group C is linked to the tetrapeptidic moiety-drug complex OP-D, resulting in the compound C-OP-D; or wherein the drug D is linked to an intermediate of the tetrapeptidic moiety OP, the intermediate of the tetrapeptidic moiety is extended with the remainder of the tetrapeptidic moiety to which the capping group C
  • the capping group C may be introduced on the tetrapeptidic moiety OP during the synthesis of OP; or the linker or spacing group may be introduced on the tetrapeptidic moiety OP during the synthesis of OP, or is introduced on the drug D (prior to linking to tetrapeptidic moiety OP).
  • Any of the above-described methods for producing a compound C-OP-D may further comprise a step of purifying the compound C-OP-D.
  • Any of the above-described methods for producing a compound C-OP-D may further comprise a step of forming a salt, crystal, co-crystal, polymorph or amorphous form of the compound C-OP-D.
  • said linking of the tetrapeptidic moiety OP with the drug D and/or capping group C may be direct, or indirect via a linker or spacing group, such as a self-immolating or self-eliminating spacer.
  • the purification strategy of the prodrug compound will obviously depend on the nature of the drug and/or of the capping group and/or of the tetrapeptidic moiety OP.
  • a skilled person will be able to design a suitable purification strategy for any possible compound according to the invention, chosing from a plethora of purification techniques that are available.
  • kits comprising a container comprising compound C-OP-D (or salt, crystal, polymporph, isomer or amorphous form thereof, or co-crystal comprising it) according to the invention or comprising a composition comprising such prodrug compound or salt thereof.
  • kit may further comprise, in the same container (holding a compound according to the invention) or in one or more separate containers, one or more further anticancer drugs, such as an antibody or fragment thereof (e.g. as described above).
  • kit may further comprise, in the same container (holding a compound according to the invention) or in one or more separate containers, one or more drug resistance reversing agents.
  • kit include one or more diagnostic agents capable of prognosing, predicting or determining the success of a therapy comprising a compound according to the invention; use instructions; one or more containers with sterile pharmaceutically acceptable carriers, excipients or diluents [such as for producing or formulating a (pharmaceutically acceptable) composition of the invention]; one or more containers with agents for ADEPT therapy; etc.
  • SEQ ID NO:X refers to a biological sequence consisting of the sequence of amino acids or nucleotides given in the SEQ. ID NO:X.
  • an antigen defined in/by SEQ ID NO:X consists of the amino acid sequence given in SEQ ID NO:X.
  • a further example is an amino acid sequence comprising SEQ ID NO:X, which refers to an amino acid sequence longer than the amino acid sequence given in SEQ ID NO:X but entirely comprising the amino acid sequence given in SEQ ID NO:X (wherein the amino acid sequence given in SEQ ID NO:X can be located N-terminally or C-terminally in the longer amino acid sequence, or can be embedded in the longer amino acid sequence), or to an amino acid sequence consisting of the amino acid sequence given in SEQ ID NO:X. All references hereinabove and hereinafter cited are incorporated in their entirety by their reference.
  • Dox Doxorubicin
  • TNBC triple negative breast cancer
  • CrC colorectal cancer
  • GBM glioblastoma multiforme
  • PrC prostate cancer
  • PaC pancreatic cancer
  • OvC ovarian cancer
  • NSCLC non-small cell lung cancer
  • PhAc phosphonoacetyl
  • ALGP alanine-leucine-glycine-proline
  • NLGP asparagine- leucine-glycine-proline
  • VAGP valine-alanine-glycine-proline
  • IAGP isoleucine-alanine-glycine- proline
  • LAGP leucine-alanine-glycine-proline
  • MLGP methionine-leucine-glycine-proline
  • AAGP alanine-alanine-glycine-proline
  • AVGP alanine-valine-glycine-proline
  • alC 5 o absolute IC 5 o
  • DMF N,N-Dimethylformamide
  • DIC /V,/V'-Diisopropylcarbodiimide
  • DIEA N,N-Diisopropylethylamine.
  • EXAMPLE 1 Chemical synthesis of auristatin- and doxorubicin-comprising prodrug compounds and of intermediates.
  • prodrugs comprising ALGP (SEQ ID NO:3) as tetrapeptidic moiety OP, phosphonacetyl as capping group C, and with drug D either being maytansine, geldanamycin, paclitaxel, docetaxel, camptothecin, vinblastine, vincristine, methotrexate, aminopterin, and amrubicin are described in Example 16 of WO 2014/102312; this procedure is fully extrapolatable to similar prodrug compounds comprising either one of the tetrapeptidic moieties AAGP (SEQ ID NO:4), AVGP (SEQ ID NO:5), MLGP (SEQ ID NO:6), NLGP (SEQ ID NO:7), IAGP (SEQ ID NO:5)
  • the linker or spacing group PABC (p-aminobenzyloxycarbamate; alternatively p- aminobenzyloxycarbonyl) is introduced between the tetrapeptidic moiety OP and the drug D; PABC is removed via a spontaneous 1,6 benzyl elimination mechanism after proteolytic removal of OP.
  • the ortho version of PABC could likewise be used, and is removed via a spontaneous 1,4-elimination.
  • the introduction of the PABC linker is described hereinafter in case of the drug D being auristatin. It can likewise be introduced in the tetrapeptidic prodrug wherein the drug D is doxorubicin (see e.g. Elsadek et al. 2010, ACS Med Chem Lett 1:234-238).
  • MMA-E (also referred to herein interchangeably as MMAE or auristatin) MMA-E was purchased from commercial supplier.
  • Compound 2 was obtained by coupling 2-phosphonoacetic acid using HATU/DIEA in DMF. Compound 2 was isolated in 19% yield after purification by prep-HPLC.
  • EXAMPLE 2 Cytotoxicity, maximal efficacy and specificity of compounds comprising a tetrapeptidic moiety and a drug.
  • SI is considered not selective towards tumor cells, while the higher the index, the better the selectivity.
  • SI is at least 2
  • these compounds could potentially have a more beneficial therapeutic window.
  • safety toward normal cells exceeded the highest concentration tested ( IC 5 o > 100 pM). As such, the selectivity is underestimated and exceeding the value reported.
  • Doxorubicin-HCI was acquired from LC-Labs (D-4000-500mg) and prodrug compounds were synthetized by WuXi AppTec (China). Stock solutions of 10 mM were dissolved in H2O and stored at -20°C until use.
  • SI Selectivity indices

Abstract

La présente invention se rapporte au domaine des composés destinés au traitement du cancer. La sélectivité de ces composés est obtenue par la présence d'une fraction tétrapeptidique spécifique permettant une libération sélective du médicament. Le médicament est en particulier un médicament cytostatique, cytotoxique ou anti-cancéreux. Un groupe de coiffage protecteur peut être introduit pour assurer la stabilité du composé dans le sang. Les fractions tétrapeptidiques fournissent à des composés promédicaments un indice de sélectivité d'au moins 2 pour au moins 2 types différents de cancers (par rapport à des cellules normales).
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Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005863A1 (fr) 1994-08-19 1996-02-29 La Region Wallonne Composes, composition pharmaceutique et dispositif de diagnostic les comprenant et leur utilisation
WO1997012624A1 (fr) 1995-10-06 1997-04-10 Merck & Co., Inc. Nouveaux peptides
US5621002A (en) 1993-09-09 1997-04-15 Behringwerke Aktiengesellschaft Prodrugs for enzyme mediated activation
WO1997014416A1 (fr) 1995-10-18 1997-04-24 Merck & Co., Inc. Conjugues utiles pour traiter l'adenome prostatique benin
WO1997034927A1 (fr) 1996-03-18 1997-09-25 Ludwig Institute For Cancer Research Proteine d'activation des fibroblastes alpha de type dimere et isolee, et ses utilisations
WO1998010651A1 (fr) 1996-09-12 1998-03-19 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
WO1998013059A1 (fr) 1996-09-27 1998-04-02 Bristol-Myers Squibb Company Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques
WO1998018493A2 (fr) 1996-10-30 1998-05-07 Merck & Co., Inc. Conjugues utilises dans le traitement du cancer de la prostate
WO1999002175A1 (fr) 1997-07-10 1999-01-21 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
WO1999028345A1 (fr) 1997-12-02 1999-06-10 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
WO2000033888A2 (fr) 1998-12-11 2000-06-15 Coulter Pharmaceutical, Inc. Composes de promedicaments et procede de preparation
US6214345B1 (en) 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
US6218519B1 (en) 1996-04-12 2001-04-17 Pro-Neuron, Inc. Compounds and methods for the selective treatment of cancer and bacterial infections
US6268488B1 (en) 1999-05-25 2001-07-31 Barbas, Iii Carlos F. Prodrug activation using catalytic antibodies
WO2001068145A2 (fr) 2000-03-15 2001-09-20 Bristol-Myers Squibb Pharma Company Medicaments antineoplastiques cibles pouvant etre clives par la peptidase et utilisation therapeutique de ces medicaments
WO2001091798A2 (fr) 2000-06-01 2001-12-06 Universite Catholique De Louvain Composes de promedicaments a activation tumorale et procedes de fabrication et d'utilisation de ces derniers
WO2001095943A2 (fr) 2000-06-14 2001-12-20 Medarex, Inc. Composes de promedicaments contenant de l'isoleucine
WO2001095945A2 (fr) 2000-06-14 2001-12-20 Medarex, Inc. Composes de promedicament a clivage enzymatique
WO2002000263A2 (fr) 2000-06-14 2002-01-03 Medarex, Inc. Composes de tripeptide pour promedicaments
WO2002007770A2 (fr) 2000-07-25 2002-01-31 Pharmacia Italia S.P.A. Conjugues polymeres d'agents antitumoraux
WO2002038590A1 (fr) 2000-11-10 2002-05-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composes antitumoraux actives par la proteine fap-alpha
WO2002100353A2 (fr) 2001-06-11 2002-12-19 Medarex, Inc. Composes pour promedicaments actives cd10
US20030096743A1 (en) 2001-09-24 2003-05-22 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
WO2003094972A2 (fr) 2002-05-10 2003-11-20 Boehringer Ingelheim Pharma Gmbh & Co Kg Promedicaments antitumoraux actives par la fap
US20040018194A1 (en) 2000-11-28 2004-01-29 Francisco Joseph A. Recombinant anti-CD30 antibodies and uses thereof
US20040052793A1 (en) 2001-02-22 2004-03-18 Carter Paul J. Caspase activivated prodrugs therapy
WO2004032828A2 (fr) 2002-07-31 2004-04-22 Seattle Genetics, Inc. Conjugues anticorps anti-cd20-medicament pour le traitement du cancer et des troubles immunitaires
US20040121940A1 (en) 2001-03-23 2004-06-24 De Groot Franciscus Marinus Hendrikus Elongated and multiple spacers in activatible produgs
US6759509B1 (en) 1996-11-05 2004-07-06 Bristol-Myers Squibb Company Branched peptide linkers
US6835807B1 (en) 1998-05-22 2004-12-28 Daiichi Pharmaceuticals Co., Ltd. Drug complex and drug delivery system
WO2006099698A2 (fr) 2005-03-24 2006-09-28 Thromb-X N.V. Nouvel anticorps anti-plgf
WO2008120098A2 (fr) 2007-04-03 2008-10-09 Diatos Promédicaments peptidiques
US20090041791A1 (en) 2004-02-23 2009-02-12 Bainian Feng Heterocyclic self-immolative Linkers and Conjugates
US20100047170A1 (en) * 2006-01-05 2010-02-25 Denmeade Samuel R Peptide Prodrugs
WO2014062587A2 (fr) 2012-10-16 2014-04-24 Genspera, Inc. Compositions anticancéreuses injectables
WO2014102312A2 (fr) 2012-12-28 2014-07-03 Life Sciences Research Partners Vzw Promédicaments minimalement toxiques

Patent Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6214345B1 (en) 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
US5621002A (en) 1993-09-09 1997-04-15 Behringwerke Aktiengesellschaft Prodrugs for enzyme mediated activation
US5962216A (en) 1994-08-19 1999-10-05 La Region Wallonne Tumor-activated prodrug compounds and treatment
WO1996005863A1 (fr) 1994-08-19 1996-02-29 La Region Wallonne Composes, composition pharmaceutique et dispositif de diagnostic les comprenant et leur utilisation
WO1997012624A1 (fr) 1995-10-06 1997-04-10 Merck & Co., Inc. Nouveaux peptides
WO1997014416A1 (fr) 1995-10-18 1997-04-24 Merck & Co., Inc. Conjugues utiles pour traiter l'adenome prostatique benin
WO1997034927A1 (fr) 1996-03-18 1997-09-25 Ludwig Institute For Cancer Research Proteine d'activation des fibroblastes alpha de type dimere et isolee, et ses utilisations
US6218519B1 (en) 1996-04-12 2001-04-17 Pro-Neuron, Inc. Compounds and methods for the selective treatment of cancer and bacterial infections
WO1998010651A1 (fr) 1996-09-12 1998-03-19 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
WO1998013059A1 (fr) 1996-09-27 1998-04-02 Bristol-Myers Squibb Company Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques
WO1998018493A2 (fr) 1996-10-30 1998-05-07 Merck & Co., Inc. Conjugues utilises dans le traitement du cancer de la prostate
US6759509B1 (en) 1996-11-05 2004-07-06 Bristol-Myers Squibb Company Branched peptide linkers
WO1999002175A1 (fr) 1997-07-10 1999-01-21 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
WO1999028345A1 (fr) 1997-12-02 1999-06-10 Merck & Co., Inc. Conjugues utiles dans le traitement du cancer de la prostate
US6835807B1 (en) 1998-05-22 2004-12-28 Daiichi Pharmaceuticals Co., Ltd. Drug complex and drug delivery system
WO2000033888A2 (fr) 1998-12-11 2000-06-15 Coulter Pharmaceutical, Inc. Composes de promedicaments et procede de preparation
US6677435B2 (en) 1999-05-25 2004-01-13 The Scripps Research Institute Prodrug activation using catalytic antibodies
US6268488B1 (en) 1999-05-25 2001-07-31 Barbas, Iii Carlos F. Prodrug activation using catalytic antibodies
WO2001068145A2 (fr) 2000-03-15 2001-09-20 Bristol-Myers Squibb Pharma Company Medicaments antineoplastiques cibles pouvant etre clives par la peptidase et utilisation therapeutique de ces medicaments
WO2001091798A2 (fr) 2000-06-01 2001-12-06 Universite Catholique De Louvain Composes de promedicaments a activation tumorale et procedes de fabrication et d'utilisation de ces derniers
WO2002000263A2 (fr) 2000-06-14 2002-01-03 Medarex, Inc. Composes de tripeptide pour promedicaments
WO2001095945A2 (fr) 2000-06-14 2001-12-20 Medarex, Inc. Composes de promedicament a clivage enzymatique
WO2001095943A2 (fr) 2000-06-14 2001-12-20 Medarex, Inc. Composes de promedicaments contenant de l'isoleucine
WO2002007770A2 (fr) 2000-07-25 2002-01-31 Pharmacia Italia S.P.A. Conjugues polymeres d'agents antitumoraux
WO2002038590A1 (fr) 2000-11-10 2002-05-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composes antitumoraux actives par la proteine fap-alpha
US20040018194A1 (en) 2000-11-28 2004-01-29 Francisco Joseph A. Recombinant anti-CD30 antibodies and uses thereof
US20040052793A1 (en) 2001-02-22 2004-03-18 Carter Paul J. Caspase activivated prodrugs therapy
US20040121940A1 (en) 2001-03-23 2004-06-24 De Groot Franciscus Marinus Hendrikus Elongated and multiple spacers in activatible produgs
WO2002100353A2 (fr) 2001-06-11 2002-12-19 Medarex, Inc. Composes pour promedicaments actives cd10
US20030130189A1 (en) 2001-09-24 2003-07-10 Senter Peter D. P-amidobenzylethers in drug delivery agents
US20030096743A1 (en) 2001-09-24 2003-05-22 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
WO2003094972A2 (fr) 2002-05-10 2003-11-20 Boehringer Ingelheim Pharma Gmbh & Co Kg Promedicaments antitumoraux actives par la fap
WO2004032828A2 (fr) 2002-07-31 2004-04-22 Seattle Genetics, Inc. Conjugues anticorps anti-cd20-medicament pour le traitement du cancer et des troubles immunitaires
US20090041791A1 (en) 2004-02-23 2009-02-12 Bainian Feng Heterocyclic self-immolative Linkers and Conjugates
WO2006099698A2 (fr) 2005-03-24 2006-09-28 Thromb-X N.V. Nouvel anticorps anti-plgf
US20100047170A1 (en) * 2006-01-05 2010-02-25 Denmeade Samuel R Peptide Prodrugs
US20140087991A1 (en) 2006-01-05 2014-03-27 The Johns Hopkins University Peptide prodrugs
WO2008120098A2 (fr) 2007-04-03 2008-10-09 Diatos Promédicaments peptidiques
WO2014062587A2 (fr) 2012-10-16 2014-04-24 Genspera, Inc. Compositions anticancéreuses injectables
WO2014102312A2 (fr) 2012-12-28 2014-07-03 Life Sciences Research Partners Vzw Promédicaments minimalement toxiques

Non-Patent Citations (62)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", August 2002
BADISA ET AL., ANTICANCER RES, vol. 29, 2009, pages 2993 - 2996
BAGSHAWE ET AL., TUMOR TARGETING, vol. 1, 1995, pages 17 - 29
BARAT ET AL., CHEM SCI, vol. 6, 2015, pages 2608 - 2613
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BEZU ET AL., FRONT IMMUNOL, vol. 6, 2015, pages 187
BOGER ET AL., BIOORG MED CHEM, vol. 3, 1995, pages 611 - 621
BOGER ET AL., PROC NATL ACAD SCI USA, vol. 92, 1995, pages 3642 - 3649
BRENNEN ET AL., J NATL CANCER INST, vol. 104, 2012, pages 1320 - 1334
CALLAHAN ET AL., J LEUKOC BIOL, vol. 94, 2013, pages 41 - 53
CHAKRAVARTY ET AL., J MED CHEM, vol. 26, 1983, pages 638 - 644
CHEN ET AL., ANAL CHIM ACTA, vol. 1033, 2018, pages 193 - 198
CHO HONG-JUN ET AL: "Theranostic iRGD peptide containing cisplatin prodrug: Dual-cargo tumor penetration for improved imaging and therapy", JOURNAL OF CONTROLLED RELEASE, vol. 300, 1 April 2019 (2019-04-01), AMSTERDAM, NL, pages 73 - 80, XP055916145, ISSN: 0168-3659, DOI: 10.1016/j.jconrel.2019.02.043 *
DAMEN ET AL., BIOORG MED CHEM, vol. 10, 2002, pages 71 - 77
DENEL-BOBROWSKA ET AL., LIFE SCI, vol. 178, 2017, pages 1 - 8
DEVY ET AL., FASEB J, vol. 18, 2004, pages 565 - 567
DUBOIS ET AL., CANCER RES, vol. 62, 2002, pages 2327 - 31
DUBOIS ET AL., EUR J CANCER, vol. 42, 2006, pages 3049 - 56
DUBOWCHIK ET AL., BIOCONJUGATE CHEM, vol. 13, 2002, pages 855 - 869
DUBOWCHIK ET AL., BIOORG MED CHEM LETT, vol. 8, 1998, pages 3341 - 3346,3347-3352
ELSADEK ET AL., ACS MED CHEM LETT, vol. 1, 2010, pages 234 - 238
ELSADEK ET AL., EUR J CANCER, vol. 46, 2010, pages 3434 - 3444
FAN ET AL., J ORGANIC CHEM, vol. 72, 2007, pages 2917 - 2928
FARQUHAR ET AL., J MED CHEM, vol. 41, 1998, pages 965 - 972
FERNANDES ET AL., CHEM COMMUN, vol. 48, 2012, pages 2083 - 2085
FERNANDEZ ET AL., J MED CHEM, vol. 44, 2001, pages 3750 - 3
GARCION ET AL., MOL CANCER THER, vol. 5, 2006, pages 1710 - 1722
GIULIANI ET AL., CANCER RES, vol. 40, 1980, pages 4682 - 4687
GREENWALD ET AL., J MED CHEM, vol. 43, 2000, pages 3093 - 3102
GROOT ET AL., ANGEW CHEM INT ED, vol. 42, 2003, pages 4490 - 4494
GUND ET AL., BIOORG MED CHEM LETT, vol. 25, 2015, pages 122 - 127
HAY ET AL., TETRAHEDRON, vol. 56, 2000, pages 645
HERSHFIELD ET AL., J AM CHEM SOC, vol. 95, 1973, pages 7359 - 69
HU ET AL., BIOORG MED CHEM LETT, vol. 20, 2010, pages 853 - 856
HUANG ET AL., J DRUG TARGET, vol. 19, 2011, pages 487 - 496
KIEVIT ET AL., J CONTROL RELEASE, vol. 152, 2011, pages 76 - 83
KOBAYASHI ET AL., CANCER RES, vol. 54, 1994, pages 2404 - 2410
KRATZ ET AL., CHEMMEDCHEM, vol. 3, 2008, pages 20 - 53
LEBEAU ET AL., MOL CANCER THER, vol. 8, 2009, pages 1378 - 1386
LI ET AL., ANGEW CHEM INT ED ENGL, vol. 57, 2018, pages 11522 - 11531
LIPPOLDGARRETT, J PHARM SCI, vol. 60, 1971, pages 1019 - 27
MADERNA ET AL., J MED CHEM, vol. 57, 2014, pages 10527 - 10534
MICHAEL B. SMITH: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2007, WILEY
PAGE ET AL., ANNU REV MED, vol. 65, 2014, pages 185 - 202
PAN ET AL., CANCER RES, vol. 63, 2003, pages 5526 - 31
RAVEL ET AL., CLIN CANCER RES, vol. 14, 2008, pages 1258 - 65
REGULATORY CLASSIFICATION OF PHARMACEUTICAL CO-CRYSTALS, August 2016 (2016-08-01)
RIVAULT ET AL., BIOORG MED CHEM, vol. 12, 2004, pages 675
ROGALSKA ET AL., PLOS ONE, vol. 13, 2018, pages e0201296
SAFAVY ET AL., J MED CHEM, vol. 42, 1999, pages 4919 - 4924
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 2012, COLD SPRING HARBOR PRESS
SHAN ET AL., J PHARM SCI, vol. 86, 1997, pages 765 - 767
TAKAHASHI ET AL., CANCER TREATMENT REV, vol. 14, 1987, pages 169 - 177
TRANOY-OPALINSKI ET AL., EUR J MED CHEM, vol. 74, 2014, pages 302 - 313
VANHENSBERGEN ET AL., BIOCHEM PHARMACOL, vol. 63, 2002, pages 897 - 908
VERT ET AL., PURE APPL CHEM, vol. 84, 2012, pages 377 - 410
WALKER ET AL., BIOORG MED CHEM LETT, vol. 14, 2004, pages 4323 - 4327
WANG ET AL., BIOORG MED CHEM, vol. 6, 1998, pages 417 - 426
WENDEL ET AL., NATURE, vol. 428, 2004, pages 332 - 337
WIDDISON ET AL., J MED CHEM, vol. 49, 2006, pages 4392 - 4408
YONEDA ET AL., BIOORG MED CHEM LETT, vol. 18, 2008, pages 1632 - 1636
ZHOU ET AL., CANCER INVEST, vol. 30, 2011, pages 119 - 125

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