WO2013182519A1 - Combinaison d'agents lysosomotropiques ou de modulation de l'autophagie et d'un inhibiteur de gsk-3 pour le traitement du cancer - Google Patents

Combinaison d'agents lysosomotropiques ou de modulation de l'autophagie et d'un inhibiteur de gsk-3 pour le traitement du cancer Download PDF

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WO2013182519A1
WO2013182519A1 PCT/EP2013/061380 EP2013061380W WO2013182519A1 WO 2013182519 A1 WO2013182519 A1 WO 2013182519A1 EP 2013061380 W EP2013061380 W EP 2013061380W WO 2013182519 A1 WO2013182519 A1 WO 2013182519A1
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gsk
inhibitor
alkyl
agent
composition
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Serdar KORUR
Florent Beaufils
Matthias Wymann
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Universitaet Basel
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to combinations of lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor, useful in the treatment of cancer, proliferative inflammatory diseases, degenerative diseases and infectious diseases.
  • Combination therapy also allows, for certain drug combinations, an optimal combined dose to minimize side effects. This is crucial as standard chemotherapeutic agents target essential cellular process such as DNA replication, cell division or induce DNA damage and thus have a general cytotoxic effect. Finally, combination treatment of two compounds may uncover unanticipated synergisms and trigger effects not induced by a single compound.
  • drugs are also used in a neoadjuvant setting, i.e. prior to surgery, to reduce the tumor mass or to improve long-term survival.
  • GSK-3 glycogen synthase 3-kinase
  • GSK-3alfa GSK-3alfa
  • GSK-3beta GSK-3beta
  • GSK-3 are implicated in a large diversity of human diseases, including nervous system disorders such as Alzheimer's disease, schizophrenia, bipolar disorder, diabetes, heart hypertrophy, renal diseases, shock and inflammation, cancers, and the like.
  • nervous system disorders such as Alzheimer's disease, schizophrenia, bipolar disorder, diabetes, heart hypertrophy, renal diseases, shock and inflammation, cancers, and the like.
  • CDKs cyclin-dependent kinases
  • GSK-3 is known for phosphorylating and thus inactivating glycogen synthase.
  • GSK-3 works in the WNT signaling pathway to phosphorylate beta-catenin.
  • GSK-3 Phosphorylation leads to ubiquitination and degradation by cellular proteases, preventing it from entering the nucleus and activating transcription factors.
  • GSK-3 When a protein called Disheveled is activated by WNT signaling, GSK-3 is inactivated, allowing beta-catenin to accumulate and effect transcription of WNT target genes.
  • GSK-3 also phosphorylates Ci in the Hedgehog (Hh) pathway, targeting it for proteolysis to an inactive form.
  • Hh Hedgehog
  • GSK-3 is unusual among the kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate, and then GSK-3 additionally phosphorylates the substrate. The consequence of GSK-3 phosphorylation is usually inhibition of the substrate. For example, when GSK-3 phosphorylates another of its substrates, the NFAT family of transcription factors, these transcription factors cannot translocate to the nucleus and are therefore inhibited.
  • GSK-3 the activity of GSK can specifically be inhibited by substances referred to herein as "inhibitor of GSK-3" or "GSK-3 inhibitor". As detailed above, the inhibition of GSK-3 leads to activation of the WNT signaling pathway.
  • a well-known inhibitor of GSK-3 is lithium, e.g. as lithium chloride.
  • the mode of inhibition is through competition for Mg 2+ .
  • the bivalent form of zinc, which mimics insulin action, has also been shown to inhibit GSK-3.
  • another metal ion, beryllium inhibits GSK-3.
  • GSK-3 inhibitors have recently been developed, most of which are ATP competitive. Summary of the Invention
  • the invention relates to pharmaceutical compositions comprising a lysosomotropic agent or agent modulating autophagy and a GSK-3 (glycogen synthase kinase 3) inhibitor, useful in the treatment of cancer, proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis, cryptosporidiosis, Dengue fever, leishmaniasis, tuberculosis and schistosomiasis, in particular cancer.
  • GSK-3 glycose kinase 3
  • the invention relates to a method of treatment of cancer, proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis, cryptosporidiosis, Dengue fever, leishmaniasis, tuberculosis and schistosomiasis, in particular cancer.
  • GSEA analysis Comparison of the GSK3 inhibitor treated data set with curated gene sets derived from literature revealed that (GSEA analysis) genes upregulated in response to GSK-3 inhibitor treatment were significantly overrepresented in gene sets related to metabolic deprivation (top panel), endoplasmic reticulum stress (middle panel) and ER stress inducing agents (bottom panel).
  • the Y-axis indicates the enrichment score (ES)
  • X-axis indicates the gene rank in the ordered dataset.
  • ATF4 target genes upon treatment with three different GSK-3 inhibitors.
  • X-axis indicates fold induction of indicated genes relative to the control.
  • FIG. 1 6-bromoindirubin-3'-acetoxime (BlO-acetoxime) and chloroquine synergize to kill LN18 glioblastoma cells in vitro.
  • Y axis indicates cell death
  • X axis indicates treatment group (Control (1 ), BlO-acetoxime 6 ⁇ (2), chloroquine 25 ⁇ (3), BlO-acetoxime 6 ⁇ and chloroquine 25 ⁇ (4)).
  • Cell death was quantified as the % of sub-G1 population 3 days after the addition of the drugs by flow cytometry using propidium iodide staining. Cell death resulting from the
  • CI combination index
  • Figure 3 Different inhibitors of lysosomal degradation and GSK-3 synergize to kill LN18 and U373 glioblastoma cells in vitro.
  • Y axis indicates cell death
  • X axis indicates treatment group
  • a and D Control (1 ), BlO-acetoxime 6 ⁇ (2), chloroquine 25 ⁇ (3), BlO-acetoxime 6 ⁇ and chloroquine 25 ⁇ (4).
  • B and E Control (1 ), BlO-acetoxime 6 ⁇ (2), 3-methyladenine 5 mM (3), BlO-acetoxime 6 ⁇ and 3-methyladenine 5 mM (4).
  • A, B, C represent LN18 and D, E, F represent U373 cells.
  • Cell death was quantified as in Figure 1 .
  • Figure 4 Different GSK-3 inhibitors and chloroquine synergize to kill LN18 glioblastoma cells in vitro.
  • Y axis indicates cell death
  • X axis indicates treatment group
  • Y axis indicates cell death
  • X axis indicates treatment group
  • GSK-3 inhibitors as understood in the present invention comprise compounds which bind to GSK-3 and decrease its kinase activity.
  • the binding of an inhibitor hinders a substrate from entering the enzyme's active site and/or prevent the enzyme from catalysing its reaction.
  • Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both.
  • a large number of drugs are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology.
  • An enzyme inhibitor used as a pharmaceutical is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme).
  • a high specificity and potency are desirable in order to minimize side effects and toxicity.
  • Inhibition as understood in the context of the present invention is based on a specific interaction between the inhibitor and GSK-3 and not just based on non-specific mechanisms (e.g. denaturation of the enzyme).
  • GSK-3 inhibitors according to the invention comprise lithium, e.g. as lithium chloride, zinc, e.g. as a Zn 2+ salt, and beryllium, e.g. as Be 2+ salt.
  • inhibitors of GSK-3 include aloisines (such as aloisine A and aloisine B), hymenialdisine (such as dibromohymenialdisine), indirubins (such as 5,5'-dibromo- indirubin), maleimides, in particular macrocyclic bisindolylmaleimides (such as Ro 31 - 8220, SB-216763, SB-415286, or 3F8), and muscarinic agonists (such as AFI02B and AFI50).
  • aloisines such as aloisine A and aloisine B
  • hymenialdisine such as dibromohymenialdisine
  • indirubins such as 5,5'-dibromo- indirubin
  • maleimides in particular macrocyclic bisindolylmaleimides (such as Ro 31 - 8220, SB-216763, SB-415286, or 3F8)
  • the GSK-3 inhibitor comprises flavopiridol, kenpaullone, alsterpaullone, azakenpaullone, pyrazolopyridine, CHIR98014, CHIR99021 , CHIR-637, CT20026, SU9516, ARA014418, and staurosporine.
  • Preferred examples of the inhibitor are selected from the group consisting of Li + , (2'Z,3'E)- 6-bromoindirubin-3'-oxime (BIO), (2Z,3'EJ-6-bromoindirubin-3'-acetoxime (BlO-acet- oxime), SB-216763 (3-(2,4-dichlorophenyl)-4-(1 -methyl-1 H-indol-3-yl)-1 H-pyrrole-2,5- dione), SB-415286 (3-[(3-chloro-4-hydroxyphenyl)amino]-4-(2-nitrophenyl)-1 H-pyrrol-2,5- dione), enzastaurin (3-(1 -methylindol-3-yl)-4-[1 -[1 -(pyridin-2-ylmethyl)piperidin-4-yl]indol- 3-yl]pyrrole-2,5-dione), L803-mts (Myr-N
  • inhibitors of GSK-3 include lithium such as lithium chloride (LiCI), TWS 1 19 (3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxyphenol di-trifluoroacetate) and 3F8 (5-ethyl-7,8-dimethoxy-1 H-pyrrolo[3,4-c]-isoquinoline-1 ,3- (2H)-dione).
  • lithium lithium chloride
  • TWS 1 19 (3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxyphenol di-trifluoroacetate)
  • 3F8 (5-ethyl-7,8-dimethoxy-1 H-pyrrolo[3,4-c]-isoquinoline-1 ,3- (2H)-dione).
  • indirubins derivatives of the bis-indole indirubin (collectively referred to as indirubins) appear as a class of original and promising tools and agents. Their moderate selectivity might be inconvenient when used as a research reagent, but their combined effects on several disease-relevant targets (in particular CDKs and GSK-3) may constitute an advantage for potential therapeutic applications.
  • indirubins 6-bromo- indirubin-3'-oxime (BIO) has been widely used to investigate the physiological role of GSK-3 in various cellular settings and to alter the fate of embryonic stem cells.
  • the GSK-3 inhibitor is a compound of formula (I): wherein X 1 and X 2 , independently of each other, are O, S, N-OR 3 , N(Z 1 ), or two groups independently selected from H, F, CI, Br, I, N0 2 , phenyl, and (CrC 6 )alkyl, and wherein R 3 is hydrogen, (C C 6 )alkyl, or (C C 6 )alkyl-C(0)-;
  • each Y independently of each other, is H, (C C 6 )alkyl, (C C 6 )alkyl-C(0)-, (C C 6 )alkyl- C(0)0-, phenyl, N(Z 1 )(Z 2 ), sulfonyl, phosphonyl, F, CI, Br, or I;
  • Z 1 and Z 2 independently of each other, are H, (d-C 6 )alkyl, phenyl, benzyl, or Z 1 and Z 2 together with the nitrogen to which they are attached represent a 5, 6, or 7-membered heterocyclyl;
  • n and m independently of each other, are 0, 1 , 2, 3, or 4;
  • R 1 and R 2 independently of each other, are H, (CrC 6 )alkyl, (CrC 6 )alkyl-C(0)-, phenyl, benzyl, or benzoyl;
  • alkyi is branched or straight-chain alkyi, optionally substituted with 1 , 2, 3, 4, or 5 OH, N(Z 1 )(Z 2 ), (CrC 6 )alkyl, phenyl, benzyl, F, CI, Br, or I; and wherein any phenyl, benzyl, or benzoyl is optionally substituted with 1 , 2, 3, 4, or 5 OH, N(Z 1 )(Z 2 ), (C C 6 )alkyl, F, CI, Br, or I;
  • X 1 is O and X 2 is N-OH, or X 1 is N-OH and X 2 is O.
  • one Y is Br.
  • one Y is Br at the 6'-position.
  • n is 0 and m is 1 , or n is 1 and m is 0.
  • R 1 and R 2 are
  • the GSK-3 inhibitor comprises 6-bromoindirubin-3'-oxime of formula
  • the GSK-3 inhibitor comprises 6-bromoindirubin-3'-acetoxime of formula (III)
  • (Ci-C 6 )alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to six carbon atoms (Ci-C 6 ).
  • (C C 6 )alkyl has one to four carbon atoms (C1-C4).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, iso-pentyl, and n-hexyl.
  • Such (d-C 6 )alkyl may be substituted as indicated.
  • heterocyclyl refers to a saturated or a partially unsaturated (i.e., having one or more double bonds within the ring) carbocyclic radical of 3 to 20 ring atoms, preferably 5, 6 or 7 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, and in which further ring atoms may be a heteroatom selected from nitrogen, oxygen, and sulphur, the remaining ring atoms being carbon atoms, where one or more ring atoms are optionally substituted independently with one or more substituents described below.
  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms, 1 nitrogen atom and 0 to 3 heteroatoms selected from N, O, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms, 1 nitrogen atom and 0 to 6 heteroatoms selected from N, O, and S), for example, a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Heterocyclyl also includes radicals wherein heterocyclic radicals are fused with a saturated or partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • heterocyclic rings include, but are not limited to, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, azetidinyl, homopiperidinyl, oxazepinyl, diazepinyl, thiazepinyl, indolinyl, pyrazolidinyl, pyrazolidinyl- imidazolinyl, and imidazolidinyl.
  • heterocyclic groups herein are optionally substituted independently with one or more substituents selected from (CrC 6 )alkyl, OH, N(Z 1 )(Z 2 ), phenyl, benzyl, F, CI, Br, I, or oxo.
  • substituents selected from (CrC 6 )alkyl, OH, N(Z 1 )(Z 2 ), phenyl, benzyl, F, CI, Br, I, or oxo.
  • substituted heterocyclic group are 2- oxopyrrolidinyl, 2-oxopiperidinyl, 4-methyl-piperazin-1 -yl, and 4-benzyl-piperazin-1 -yl.
  • 6-bromoindirubin- 3'-oxime 6-bromoindirubin-3'-acetoxime
  • 6-bromoindirubin-3'-acetoxime BlO-acetoxime
  • TDZD-8 6-bromoindirubin-3'-acetoxime
  • L803-mts lithium carbonate, valproic acid, lithium, divalproex, tideglusib (NP031 1 12), and enzastaurin hydrochloride (LY317615).
  • Lysosomotropic agent is defined herein as a compound, which diffuses into cellular lysosomes, may cause a decrease in the lysosome transmembrane proton gradient, and may increase the pH inside the organelle. Lysosomotropic agents are known to increase the internal pH of acidic vesicles and include the compounds ammonium chloride, monensin, nigericin, methylamine and ethylamine.
  • ammonium chloride, methylamine and ethylamine are less suitable as components of the inventive combinations with a GSK-3 inhibitor, and are not part of the preferred combinations.
  • the lysosomotropic agent is selected from chlorpromazine, LysoTracker® green (7-(3- (2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-1 ,3-dimethyl-2,5-dihydro-1 H- dipyrrolo[1 ,2-c:1 ',2'-f][1 ,3,2]diazaborinin-4-ium-5-uide), LysoTracker® red (7-(3-(2- (dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(1 H-pyrrol-2-yl)-2,5-dihydro-1 H- dipyrrolo[1 ,2-c:1 ',2'-f][1 ,3,2]diazaborinin-4-ium-5-uide), amantadine, 4-aminoquinoline, amiodarone
  • the lysosomotropic agent is selected from chlorpromazine,
  • LysoTracker® green (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-1 ,3- dimethyl-2,5-dihydro-1 H-dipyrrolo[1 ,2-c:1 ',2'-f][1 ,3,2]diazaborinin-4-ium-5-uide),
  • LysoTracker® red (7-(3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(1 H- pyrrol-2-yl)-2,5-dihydro-1 H-dipyrrolo[1 ,2-c:1 ',2'-f][1 ,3,2]diazaborinin-4-ium-5-uide), amantadine, 4-aminoquinoline, amiodarone, amodiaquine, azithromycin, chloroquine, clindamycin, N-(3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl)-N-methylamine dihydrochloride (DAMP), N,N'-bis(2,3-butadienyl)-1 ,4-butanediamine dihydrochloride, imipramine, 3-methyladenine, monensin,
  • amodiaquine (4-[(7-chloroquinolin-4-yl)amino]- 2-(diethylaminomethyl)phenol; CAS Registry No. 86-42-0), azithromycin ⁇ (2R,3R,4R,5R, 8R, 10R, 11R, 13S, 14R)A 1 -[ ⁇ 2S,3 ?,4S,6 ?
  • chloroquine N'-(7-chloroquinolin-4-yl)-N,N-diethyl- pentane-1 ,4-diamine; CAS Registry No. 54-05-7
  • chlorpromazine (3-(2-chloro-10H- phenothiazin-10-yl)-N,N-dimethyl-propan-1 -amine; CAS Registry No. 50-53-3)
  • citalopram (1 -(3-dimethylaminopropyl)-1 -(4-fluorophenyl)-1 ,3-dihydroisobenzofuran-5-carbonitrile; CAS Registry No.
  • DAMP N-(3-[(2,4-dinitrophenyl)-amino]-propyl)-N-(3-aminopropyl)-N-methyl-amine dihydrochloride, fluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1 - amine; CAS 54910-89-3), flupentixol (2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]- propyl]piperazin-1 -yl]ethanol; CAS Registry No.
  • levomepromazine (('2/?)-3-(2-methoxyphenothiazine-10-yl-)-N,N,2-trimethyl- propanamine; CAS Registry No. 60-99-1 ), LysoTracker® green (7-(3-(2-(dimethylamino)- ethylamino)-3-oxopropyl)-5,5-difluoro-1 ,3-dimethyl-2,5-dihydro-1 H-dipyrrolo[1 ,2-c:1 ',2'- f][1 ,3,2]diazaborinin-4-ium-5-uide; CAS Registry No.
  • LysoTracker® red 7- (3-(2-(dimethylamino)ethylamino)-3-oxopropyl)-5,5-difluoro-3-(1 H-pyrrol-2-yl)-2,5-dihydro- 1 H-dipyrrolo[1 ,2-c:1 ',2'-f][1 ,3 ,2]diazaborinin-4-ium-5-uide; CAS-No. 231946-72-8), meclofenoxate (2-dimethylaminoethyl 2-(4-chlorophenoxy)acetate; CAS Registry No.
  • monensin (4-[2-[5-ethyl-5-[5-[6- hydroxy-6-(hydroxymethyl)-3,5-dimethyl-oxan-2-yl]-3-methyl-oxolan-2-yl]oxolan-2-yl]-9- hydroxy-2,8-dimethyl-1 ,6-dioxaspiro[4.5]dec-7-yl]-3-methoxy-2-methyl-pentanoic acid; CAS Registry No. 22373-78-0), monodansyl-cadaverine (N-(5-aminopentyl)-5-(dimethyl- amino)naphthalene-1 -sulfonamide; CAS Registry No.
  • perphenazine (2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1 -yl]ethanol; CAS Registry No. 58-39-9), phenylalanine methyl ester (methyl ( ⁇ S ⁇ -amino-S-phenyl- propanoate hydrochloride; CAS Registry No. 2577-90-4), piperazine (CAS Registry No. 1 10-85-0), primaquine (N-(6-methoxyquinolin-8-yl)pentane-1 ,4-diamine; CAS Registry No.
  • prochlorperazine (2-chloro-10-[3-(4-methyl-1 -piperazinyl)propyl]-10H-pheno- thiazine; CAS Registry No. 58-38-8), promazine (N,N-dimethyl-3-(10H-phenothiazin-10- yl)propan-1 -amine; CAS Registry No. 58-40-2), propranolol (1 -(isopropylamino)-3- (naphthalen-1 -yloxy)propan-2-ol; CAS Registry No.
  • suramin (8-[[4-methyl-3-[[3- [[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-1 -yl)-carbamoyl]-phenyl]carbamoyl]-phenyl]- carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1 ,3,5-trisulfonic acid; CAS Registry No. 145-63-1 ), thioridazine (10- ⁇ 2-[1 -methylpiperidin-2-yl]ethyl ⁇ -2-methylsulfanyl- phenothiazine; CAS Registry No.
  • thioridazine (10- ⁇ 2-[1 -methylpiperidin-2-yl]- ethyl ⁇ -2-methylsulfanyl-phenothiazine; CAS Registry No. 50-52-2), tributylamine (CAS
  • lysosomotropic agents of the Examples in particular chloroquine, hydroxychloroquine, 3-methyladenine, quinacrine, mefloquine, monensin and bafilomycin A1 .
  • Autophagy-lysosome pathway is one of the major route for protein and organelle clearance in eukaryotic cells.
  • Mammalian lysosomes can degrade substrates like protein complexes and organelles.
  • the bulk degradation of cytoplasmic proteins or organelles is largely mediated by macroautophagy, generally referred to as autophagy (Klionsky et al., Science 290:1717-20, 2000).
  • Autophagy is the process by which cells cannibalize cellular elements (e.g., proteins, organelles).
  • Autophagy is the cell's major regulated mechanism for degrading long- lived proteins and the only known pathway for degrading organelles. Downstream of TOR kinase, there are approximately seventeen gene products essential for autophagy and related pathways in yeast.
  • the following compounds are late inhibitors of autophagosome-lysosome fusion: cefamandole, monensin, astemizole, spiramycin, ('7S,9R)-beta-hydrastine, carnitine, tomatine, K252A, atranorin, tetrandrine, amlodipine, benzyl isothiocyanate, pristimerin, homochlorcyclizine (e.g., homochlorcyclizine dihydrochloride), fluoxetine (e.g., fluoxetine hydrochloride), bafilomycin A 1 , wiskostatin, monensin, quinacrine, nocodazole, vinblastine, colchicine, puromycin, bepridil, spiramycin, migericin, 2-methylcinngel, amiprilose, carnitine, tyrphostin 9, salinomycin, PP 1 , lavendus
  • the kinase inhibitors sunitinib, UCN01 , PKC412, and ruboxistaurin are likewise considered as inhibitors of autophagy.
  • vinblastine is excluded from the present definition of inhibitors of autophagy in combination with a GSK-3 inhibitor due to its multiple mechanism of action.
  • modulators i.e., both promoters and inhibitors
  • Other modulators include LY-83583, rapamycin, hydroxychloroquine, pimozide, gramicidin, manoalide, doxorubicin (e.g., doxorubicin hydrochloride), daunorubicin (e.g., daunorubicin hydrochloride), rhodo- myrtoxin B, isogedunin, solanine alpha (solanidine), ellipticine, amiprilose, gentian violet, wiskostatin, manumycin A, tetrandrine, trimethobenzamide, tamoxifen, (e.g., tamoxifen citrate), RWJ-60475-(AM)3, amphotericin B, hexetidine, maprotiline (e.g., maprotiline hydrochloride), D609, G06976, nigericin, methyl
  • Preferred modulators therefore include LY-83583, rapamycin, hydroxychloroquine, pimozide, gramicidin, manoalide, doxorubicin (e.g., doxorubicin hydrochloride), daunorubicin (e.g., daunorubicin
  • maprotiline e.g., maprotiline
  • compositions according to the invention are, for example, compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration.
  • the compositions comprise a lysosomotropic agent or agents modulating autophagy and a GKS-3 inhibitor, alone or, preferably, together with a pharmaceutically acceptable carrier.
  • the dosage of the combination of a lysosomotropic agent or agents modulating autophagy and the GSK-3 inhibitor depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual
  • compositions comprise from approximately 1 % to approximately 90% of the combination of a lysosomotropic agent or agents modulating autophagy and a GSK- 3 inhibitor.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity- increasing agents, typically sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween 80 ® (polyoxy- ethylene(20)sorbitan mono-oleate).
  • Suspensions in oil comprise as the oil component the vegetable, synthetic, or semisynthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms.
  • the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and groundnut oil are especially useful.
  • the manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • Suitable carriers for preferred solid oral dosage forms are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above- mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl- methylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the combination of a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitor.
  • concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropy
  • compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the combination of a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitor in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the combination of a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitor is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suppository bases are, for example, natural or synthetic triglycerides, paraffin
  • hydrocarbons polyethylene glycols or higher alkanols.
  • aqueous solutions of a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium
  • the combination of a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitor, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • compositions comprising a GSK-3 inhibitor and a lysosomotropic agent or agents modulating autophagy according to the invention show therapeutic efficacy against different types of cancer including carcinomas, sarcomas, gliomas, leukemias, lymphomas, e.g.
  • epithelial neoplasms squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, naevi and melanomas, soft tissue tumors including sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal n
  • chondromatous neoplasms giant cell tumors, miscellaneous bone tumors, gliomas, glioblastomas, oligodendrogliomas, neuroepitheliomatous neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin ' s and non-Hodgkin " s lymphomas, other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative diseases, leukemias including acute and chronic leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.
  • a GSK-3 inhibitor and a lysosomotropic agent or agents modulating autophagy show therapeutic efficacy against proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis, cryptosporidiosis, Dengue fever, leishmaniasis, tuberculosis and schistosomiasis.
  • the combination of a GSK-3 inhibitor and a lysosomotropic agent or agents modulating autophagy, and pharmaceutical compositions comprising a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor according to the invention may be applied in the form of fixed combinations.
  • Such fixed combination may contain a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor in a relative molecular amount (Mol per Mol) of between 50 to 1 and 1 to 50, preferably between 5 to 1 and 1 to 5, such as a combination of 1 to 1.
  • the combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor may be applied in two different, separate pharmaceutical compositions, optionally being provided together in a kit.
  • the administration of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor may also be staggered, or the compounds may be given independently of one another within a reasonable time window.
  • the combination of a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitors and pharmaceutical compositions comprising a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitors may be administered especially for cancer therapy in combination with radiotherapy, immunotherapy, surgical intervention, or a combination of these.
  • the present invention relates furthermore to a method for the treatment of cancer which comprises administering a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor in a quantity effective against said disease, to a warmblooded animal requiring such treatment.
  • a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitors can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment.
  • the daily dose administered is from approximately 0.1 g to approximately 4 g, preferably from approximately 0.2 g to approximately 2 g, of a combination of the present invention.
  • the invention relates to the use of a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor and of pharmaceutical compositions comprising a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor for the treatment of cancer, in particular for the treatment of the particular cancers mentioned above.
  • the invention relates to the use of a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor and of pharmaceutical compositions comprising a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor for the treatment of carcinomas, sarcomas, leukemias, myelomas, lymphomas, and cancers of the nervous system.
  • the invention relates to the use of a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor and of pharmaceutical compositions comprising a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor for achieving treatment of proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis,
  • a lysosomotropic agent or agents modulating autophagy and GSK-3 inhibitor depend on the type of cancer or other disease, the severity and progress of the disease, and the particular condition of the patient to be treated, and has to be determined accordingly by the medical doctor responsible for the treatment.
  • the invention further relates to the use of a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor for the preparation of a
  • compositions for the treatment of cancer proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis, cryptosporidiosis, Dengue fever, leishmaniasis, tuberculosis and schistosomiasis, as explained above.
  • the invention provides a method for treatment of cancer, proliferative inflammatory diseases, degenerative diseases and infectious diseases including malaria, hepatitis A to C, HIV, African trypanosomiasis, cryptosporidiosis, Dengue fever, leishmaniasis, tuberculosis and schistosomiasis, which comprises administering a combination of a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor or of a pharmaceutical composition comprising a lysosomotropic agent or agents modulating autophagy and a GSK-3 inhibitor, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • Glioblastoma and melanoma cell lines were grown at 37°C in a 5% C0 2 atmosphere in DMEM (U87, LN18, U373, LN229, A2058, B16) supplemented with 10% heat-inactivated FCS, 1 x alanyl-glutamine, and 1 x penicillin-streptomycin (all from Sigma) and 1 x nonessential amino acids (from AMI MED).
  • BS287 ex vivo glioblastoma cells were cultured in Neurobasal medium (Invitrogen) supplemented with basic fibroblast growth factor (20 ng/ml, Invitrogen), epidermal growth factor (20 ng/ml, R&D Systems), B27 (1x) and N2 supplement (0.5x) (Invitrogen).
  • BlO-acetoxime (from TOCRIS) is dissolved in DMSO at 24 mM
  • BEZ235 from Novartis
  • DMSO 10 mM and stored at -20°C, further dilutions were performed in cell culture media freshly before each experiment. Drug concentrations used are indicated in the figure legends.
  • Other compounds used were bafilomycin A1 , chloroquine and 3-methyladenine (Sigma), L803mts (Genemed USA), TDZD-8 (EMD Millipore), and BEZ235 (from Novartis).
  • Cells at the logarithmic phase of growth were trypsinized and plated at a concentration of 15x10 3 cells/cm 2 . Drugs were added 24 hours later. After 3 days of exposure to the compounds cells were trypsinized and prepared for cell cycle and apoptosis analysis. For cell death evaluation, cells were fixed and permeabilized in 70% cold ethanol for 60 minutes at 4°C, and subsequently washed with PBS.
  • the pellet was resuspended in PBS containing 50 ⁇ g mL propidium iodide and 10 ⁇ g mL DNase-free RNase and incubated for 8 h at 4°C before fluorescence-activated cell sorting data acquisition (FACSCalibur, Becton Dickinson) and % of cells in sub-G1 cell determined.
  • Apoptosis resulting from the combination of two drugs was analyzed for each cell line using CalcuSyn Software (Biosoft) to generate a combination index (CI).
  • a CI greater than one indicates antagonism.
  • a CI of one indicates an additive effect.
  • a CI less than one indicates synergism. Specifically, a value between 0.85 and 0.90 indicate slight synergism, between 0.70 and 0.85 indicates a moderate synergism, between 0.30 and 0.70 indicates synergism, between 0.10 and 0.30 indicates strong synergism, and ⁇ 0.1 indicates a very strong synergism.

Abstract

L'invention concerne des combinaisons d'un agent lysosomotropique ou d'agents de modulation de l'autophagie, tel que chloroquine, 3-méthyladénine ou bafilomycine A1, et un inhibiteur de GSK-3, tel que le (2'Z,3'E)-6-bromoindirubin-3'-acétoxime, TDZD-8 ou L803-mts. Ces compositions sont utiles dans le traitement du cancer, de maladies inflammatoires prolifératives, de maladies dégénératives et de certaines maladies infectieuses, de préférence le cancer. La survie de cellules tumorales est particulièrement dépendante de la fonction correcte du reticulum endoplasmique.
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WO2016008977A1 (fr) * 2014-07-16 2016-01-21 Irbm Science Park S.P.A. Utilisation de perhexiline
US10624880B2 (en) 2015-04-20 2020-04-21 Tolero Pharmaceuticals, Inc. Predicting response to alvocidib by mitochondrial profiling
US10562925B2 (en) 2015-05-18 2020-02-18 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs having increased bioavailability
US10835537B2 (en) 2015-08-03 2020-11-17 Sumitomo Dainippon Pharma Oncology, Inc. Combination therapies for treatment of cancer
US10568887B2 (en) 2015-08-03 2020-02-25 Tolero Pharmaceuticals, Inc. Combination therapies for treatment of cancer
US10682356B2 (en) 2015-08-03 2020-06-16 Tolero Pharmaceuticals, Inc. Combination therapies for treatment of cancer
WO2017027984A1 (fr) * 2015-08-20 2017-02-23 Simon Fraser University Composés et procédés de traitement anticancéreux par l'inhibition d'atg4b et le blocage de l'autophagie
WO2017069960A1 (fr) * 2015-10-19 2017-04-27 The Scripps Research Institute Inhibiteurs du métabolisme du soufre à activité bactéricide puissante contre la m.tuberculose mdr ou xdr
JP2019502671A (ja) * 2015-12-01 2019-01-31 ▲海▼▲門▼雨霖▲細▼胞科技有限▲責▼任公司 小分子組成物を用いてヒト腫瘍細胞を非腫瘍形成性細胞に直接リプログラミングすることを誘導する方法
US11279694B2 (en) 2016-11-18 2022-03-22 Sumitomo Dainippon Pharma Oncology, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
US10422788B2 (en) 2016-12-19 2019-09-24 Tolero Pharmaceuticals, Inc. Profiling peptides and methods for sensitivity profiling
US11497756B2 (en) 2017-09-12 2022-11-15 Sumitomo Pharma Oncology, Inc. Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
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US11530231B2 (en) 2018-12-04 2022-12-20 Sumitomo Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
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