WO2024003408A1 - Inhibiteurs à petites molécules de l'interaction frs2-fgfr - Google Patents

Inhibiteurs à petites molécules de l'interaction frs2-fgfr Download PDF

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WO2024003408A1
WO2024003408A1 PCT/EP2023/068173 EP2023068173W WO2024003408A1 WO 2024003408 A1 WO2024003408 A1 WO 2024003408A1 EP 2023068173 W EP2023068173 W EP 2023068173W WO 2024003408 A1 WO2024003408 A1 WO 2024003408A1
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cancer
alkyl
independently selected
compound
formula
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PCT/EP2023/068173
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English (en)
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Gisbert Schneider
Cyrill BRUNNER
Martin Baumgartner
Karthiga Santhana KUMAR
Oliver ZERBE
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Universität Zürich
ETH Zürich
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Publication of WO2024003408A1 publication Critical patent/WO2024003408A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to small-molecule inhibitors of the FRS2-FGFR interaction.
  • the present invention relates the small-molecule inhibitors for use as a medicament and for use in cancer treatment or prevention.
  • Metastasis the dissemination and growth of neoplastic cells in an organ distant from that in which they originated, causes as much as 90% of cancer-associated mortality.
  • Effective cancer therapy is largely dependent on the capability to prevent metastasis specifically and less toxic, targeted anti-metastatic therapies are urgently needed.
  • An important and fundamental cause of metastasis in most of all solid tumours is the deregulated motile behaviour of the cancer cells.
  • the microenvironment shapes cell behaviour and determines metastatic outcomes of tumours.
  • Kumar et al. (Cell Reports, 2018, vol. 23, issue 13, P3798-3812) addressed how microenvironmental cues control tumour cell invasion in pediatric brain tumour, medulloblastoma (MB).
  • TGF-p regulates pro-migratory bFGF function in a context-dependent manner.
  • the non-canonical TGF-p pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype.
  • FRS2 FGF receptor
  • TGF-p counters inactivation of FRS2 and restores pro-migratory signalling.
  • the objective of the present invention is to provide means and methods to provide small-molecule inhibitors of the FRS2-FGFR interaction. This objective is attained by the subject-matter of the independent claims of the present specification. Summary of the Invention
  • a first aspect of the invention relates to a compound of the general formula (100) wherein - Y is O or S;
  • - - X is N or CH
  • L is a linker selected from
  • n 0, 1 , 2, 3 or 4, particularly n is 1 or 2, more particularly n is 2; each R 1 is independently selected from an unsubstituted or substituted Ci-Ce alkyl,
  • each R 1 is independently selected from OR°, COOR A , COOH and OH; or two R 1 form a C4-C8 cyclo-alkyl or a 4- to 8-membered heterocycle, particularly two R 1 form a Cs-Ce cyclo-alkyl or a 5- to 6-membered heterocycle, wherein the cyclo-alkyl or the heterocycle is unsubstituted or substituted with C1-C3 alkyl, NO 2 , COOR A , OR° CN, halogen, NR N1 R N2 , SO 2 R S with R N1 , R N2 , R°, R A , and R s being independently selected from H, and
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a second aspect relates to a compound as described in the first aspect for use as a medicament.
  • a third aspect of the invention relates to a compound as described in the first aspect for use in treatment or prevention of cancer.
  • said cancer is selected from ependymoma, prostate cancer, esophageal cancer, thyroid cancer, hepatocellular carcinoma, testicular cancer, pediatric brain tumour, medulloblastoma, rhabdomyosarcoma, gastric cancer, pulmonary pleomorphic carcinoma, breast cancer, non-small cell lung cancer, liposarcoma, cervical cancer, colorectal cancer, melanoma, multiple myeloma, endometrial cancer, bladder cancer, glioblastoma, squamous cell carcinoma of the lung, ovarian cancer, head and neck cancer, and pancreatic cancer, sarcoma.
  • said cancer is selected from bladder cancer, multiple myeloma, gastric cancer, pediatric brain tumour, medulloblastoma, glioblastoma, ependymoma, and sarcoma. In certain embodiments, said cancer is selected from bladder cancer, colorectal cancer, pediatric brain tumour, medulloblastoma, multiple myeloma, and gastric cancer.
  • a fourth aspect of the invention relates to a compound as described in the first aspect use in treatment or prevention of metastasis.
  • said metastasis arises from a cancer selected from bladder cancer, colorectal cancer, pediatric brain tumour, medulloblastoma, multiple myeloma, and gastric cancer.
  • a fifth aspect of the invention relates to a compound as described in the first aspect for use as an angiogenesis antagonist.
  • FGFR fibroblast growth factor receptor
  • FRS2 FGFR substrate 2
  • PTB c-terminal phospho-tyrosine binding
  • Binding site 1 is not involved in FGFR binding and located below the interaction site of FGFR’s N-terminus with FRS2.
  • Binding site 2 is the extended surface area interacting with FGFR’s C-terminal end.
  • the mechanism of compound-target interaction, conformational change in the target domain and transmission blockade is unique and does not depend on receptor tyrosine kinase inhibition.
  • FRS2 does not have any shared protein domains with other adapter proteins.
  • the compounds also interfere specifically with those FGFR functions that are particularly relevant for tumorigenesis and tumor progression.
  • the compounds In contrast to existing FGFR targeting strategies, the compounds also interfere specifically with those FGFR functions that are particularly relevant for tumorigenesis and tumor progression, such as proliferation, migration and invasion and angiogenesis.
  • FRS2- FGFR interaction is altered in many types of cancer, for example in prostate cancer (Yang, F. et al. Cancer Res 73, 3716-3724, 2013, Liu J et al. Oncogene. 2016 Apr 7;35(14):1750-9), esophageal cancer (Nemoto, T., Ohashi, K., Akashi, T., Johnson, J. D. & Hirokawa, K. Pathobiology 65, 195-203, 1997), thyroid cancer (St Bernard, R. et al.
  • a Cv-Ce alkyl in the context of the present specification signifies a saturated linear or branched hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms, wherein one carbon-carbon bond may be unsaturated and/or one CH2 moiety may be exchanged for oxygen (ether bridge) or nitrogen (NH, or NR with R being methyl, ethyl, or propyl; amino bridge).
  • Ci-Ce alkyl include the examples given for C1-C4 alkyl above, and additionally 3-methylbut-2- enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1 ,1- dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2-dimethylpropyl, pent-4-inyl, 3-methyl-2-pentyl, and 4- methyl-2-pentyl.
  • a C5 alkyl is a pentyl or cyclopentyl moiety and a Ce alkyl is a hexyl or cyclohexyl moiety.
  • C3-C7 cycloalkyl in the context of the present specification relates to a saturated hydrocarbon ring having 3, 4, 5, 6 or 7 carbon atoms, wherein in certain embodiments, one carbon-carbon bond may be unsaturated.
  • Non-limiting examples of a C3-C7 cycloalkyl moiety include cyclopropanyl (-C3H5), cyclobutanyl (-C4H7), cyclopentenyl (C5H9), and cyclohexenyl (CeHn) moieties.
  • a cycloalkyl is substituted by one Ci to C4 unsubstituted alkyl moiety.
  • a cycloalkyl is substituted by more than one Ci to C4 unsubstituted alkyl moieties.
  • carbocycle in the context of the present specification relates to a cyclic moiety composed of carbon and hydrogen atoms only.
  • An aromatic carbocycle is also named aryl.
  • a non-aromatic carbocycle is also named cycloalkyl.
  • heterocycle in the context of the present specification relates to a cyclic moiety, wherein at least one ring atom is replaced or several ring atoms are replaced by a nitrogen, oxygen and/or sulphur atom.
  • An aromatic heterocycle is also named heteroaryl.
  • a non- aromatic heterocycle is a cycloalkyl, wherein at least one ring atom is replaced or several ring atoms are replaced by a nitrogen, oxygen and/or sulphur atom.
  • a 6-membered heterocycle may be, for example, tetrahydropyran or dioxane.
  • heterobicycle in the context of the present specification relates to two directly connected cycles, wherein at least one ring atom is replaced or several ring atoms are replaced by a nitrogen, oxygen and/or sulphur atom.
  • a heterobicycle is composed of two heterocycles or of one heterocycle and one carbocycle.
  • unsubstituted C n alkyl when used herein in the narrowest sense relates to the moiety -C n H2n- if used as a bridge between moieties of the molecule, or -C n H2n+i if used in the context of a terminal moiety.
  • unsubstituted C n alkyl and substituted C n alkyl include a linear alkyl comprising or being linked to a cyclical structure, for example a cyclopropane, cyclobutane, cyclopentane or cyclohexane moiety, unsubstituted or substituted depending on the annotation or the context of mention, having linear alkyl substitutions.
  • the total number of carbon and -where appropriate- N, O or other hetero atom in the linear chain or cyclical structure adds up to n.
  • Me is methyl CH3, Et is ethyl -CH2CH3, Prop is propyl -(CH 2 ) 2 CH3 (n-propyl, n-pr) or -CH(CH 3 ) 2 (iso-propyl, i-pr), but is butyl -C 4 H 9 , -(CH 2 ) 3 CH3, -CHCH3CH2CH3, -CH 2 CH(CH 3 )2 or -C(CH 3 ) 3 .
  • substituted alkyl in its broadest sense refers to an alkyl as defined above in the broadest sense, which is covalently linked to an atom that is not carbon or hydrogen, particularly to an atom selected from N, O, F, B, Si, P, S, Cl, Br and I, which itself may be -if applicable- linked to one or several other atoms of this group, or to hydrogen, or to an unsaturated or saturated hydrocarbon (alkyl or aryl in their broadest sense).
  • substituted alkyl refers to an alkyl as defined above in the broadest sense that is substituted in one or several carbon atoms by groups selected from amine NH2, alkylamine NHR, imide NH, alkylimide NR, amino(carboxyalkyl) NHCOR or NRCOR, hydroxyl OH, oxyalkyl OR, oxy(carboxyalkyl) OCOR, carbonyl O and its ketal or acetal (OR)2, nitril CN, isonitril NC, cyanate CNO, isocyanate NCO, thiocyanate CNS, isothiocyanate NCS, fluoride F, choride Cl, bromide Br, iodide I, phosphonate PO3H2, PO3R2, phosphate OPO3H2 and OPO3R2, sulfhydryl SH, suflalkyl SR, sulfoxide SOR, sulfonyl SO
  • hydroxyl substituted group refers to a group that is modified by one or several hydroxyl groups OH.
  • amino substituted group refers to a group that is modified by one or several amino groups NH2.
  • Non-limiting examples of amino-substituted alkyl include -CH2NH2, -CH2NHMe, -CH2NHEt,
  • CH 2 CH(CH 2 NHEt) 2 for terminal moieties and -CH2CHNH2-, -CH 2 CHNHMe-, -CH 2 CHNHEt- for an amino substituted alkyl moiety bridging two other moieties.
  • Non-limiting examples of hydroxy-substituted alkyl include -CH2OH, -(CH 2 )2OH, -(CH2)3OH, -CH 2 CH(OH)CH 3 , -(CH 2 ) 4 OH, -CH(CH 2 OH)CH 2 CH 3 , -CH 2 CH(CH 2 OH)CH 3 , -CH(OH)(CH 2 ) 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)(CH 2 )2OH and -CH 2 CH(CH 2 OH) 2 for terminal moieties and -CHOH-, -CH2CHOH-, -CH 2 CH(OH)CH 2 -, -(CH 2 ) 2 CHOHCH2-, - CH(CH 2 OH)CH 2 CH 2 -, -CH 2 CH(CH 2 OH)CH 2 -, -CH(OH)(CH 2 CHOH-, -CH(OH)(CH 2 CHOH-,
  • sulfoxyl substituted group refers to a group that is modified by one or several sulfoxyl groups -SO2R, or derivatives thereof, with R having the meaning as laid out in the preceding paragraph and different from other meanings assigned to R in the body of this specification.
  • amine substituted group refers to a group that is modified by one or several amine groups -NHR or -NR2, or derivatives thereof, with R having the meaning as laid out in the preceding paragraph and different from other meanings assigned to R in the body of this specification.
  • carbonyl substituted group refers to a group that is modified by one or several carbonyl groups -COR, or derivatives thereof, with R having the meaning as laid out in the preceding paragraph and different from other meanings assigned to R in the body of this specification.
  • An ester refers to a group that is modified by one or several ester groups -CO2R, with R being defined further in the description.
  • An amide refers to a group that is modified by one or several amide groups -CONHR, with R being defined further in the description.
  • halogen-substituted group refers to a group that is modified by one or several halogen atoms selected (independently) from F, Cl, Br, I.
  • fluoro substituted alkyl refers to an alkyl according to the above definition that is modified by one or several fluoride groups F.
  • fluoro-substituted alkyl include -CH 2 F, -CHF 2 , -CF 3 , -(CH 2 ) 2 F, -(CHF) 2 H, -(CHF) 2 F, -C 2 F 5 , -(CH 2 ) 3 F, -(CHF) 3 H, - (CHF) 3 F, -C 3 F 7 , -(CH 2 ) 4 F, -(CHF) 4 H, -(CHF) 4 F and -C 4 F 9 .
  • Non-limiting examples of hydroxyl- and fluoro-substituted alkyl include -CHFCH 2 OH, - CF 2 CH 2 OH, -(CHF) 2 CH 2 OH, -(CF 2 ) 2 CH 2 OH, -(CHF) 3 CH 2 OH, -(CF 2 ) 3 CH 2 OH, -(CH 2 ) 3 OH, -CF 2 CH(OH)CH 3 , -CF 2 CH(OH)CF 3 , -CF(CH 2 OH)CHFCH 3 , and -CF(CH 2 OH)CHFCF 3 .
  • aryl in the context of the present specification signifies a cyclic aromatic C5-C10 hydrocarbon.
  • aryl include, without being restricted to, phenyl and naphthyl.
  • a heteroaryl is an aryl that comprises one or several nitrogen, oxygen and/or sulphur atoms.
  • heteroaryl include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.
  • An aryl or a heteroaryl in the context of the specification additionally may be substituted by one or more alkyl groups.
  • the C x designates the number of C atoms between the amide group and the ether group.
  • the term pharmaceutical composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to the invention is provided in a form suitable for topical, parenteral or injectable administration.
  • the term pharmaceutically acceptable earner includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington: the Science and Practice of Pharmacy, ISBN 0857110624).
  • a first aspect of the invention relates to a compound of the general formula (100) wherein
  • - - X is N or CH
  • L is a linker selected from
  • each R 1 is independently selected from an unsubstituted or substituted Ci-Ce alkyl, OH, OR°, COOR A , CN, NO 2 , halogen, NR N1 R N2 , SO 2 R s , with R N1 , R N2 , R s , R A , and R°being independently selected from H, and Ci-Ce alkyl; particularly each R 1 is independently
  • An amine function in the linker L is beneficial, as it increases the solubility of the compound.
  • the compound is of the general formula (201) or (202) wherein
  • X, L, R 2 , and m have the same meanings as defined above; k is 0, 1 , or 2; each R 3 is independently selected from Ci- Cs-alkyl, OR°, COOR A , CN, NO2, halogen, NR N1 R N2 , with R N1 , R N2 , R A , and R° being independently selected from H, and C1-C3 alkyl;
  • V 1 and V 2 are independently selected from CH2, CHR 3 , O, S, NH, and NR 3 ; with the proviso that at least one of R 3 , V 1 and V 2 comprises a heteroatom;
  • - W is selected from -CH 2 -, -CHR 3 - , -CH2-CH2-, -CHR 3 -CH 2 -, -CH2-CHR 3 , and - CHR 3 -CHR 3 -.
  • the heteroatom in at least one of R 3 , V 1 and V 2 is important to stabilize the interaction of this moiety with the target protein.
  • the compound is of the general formula (300) wherein
  • R 2A and R 2B are selected from H and C1-C3 alkyl, particularly R 2A and R 2B are selected from H and methyl.
  • L is according to formula (401), (402), or (403), (40T), (402’), or (403’) particularly L is according to formula (401), (402), or (403), wherein
  • Q is N or CH, particularly Q is N;
  • R L is selected from H and a C1-C3 alkyl, particularly R L is methyl;
  • R N is selected from H, C1-C3 alkyl; -(Ci-C4)-NR N1 R N2 , with R N1 and R N2 being independently selected from H, and C1-C3 alkyl.
  • V 1 and V 2 have the same meanings as defined above, particularly at least one of V 1 and V 2 is independently selected from O, S, and NH, particularly at least one of V 1 and V 2 is O,
  • R 3A and R 3B are independently selected from H, Ci- Cs-alkyl, OR°, COOR A , CN, NO2, halogen, NR N1 R N2 , with R N1 , R N2 , R A , and R° being independently selected from H, and C1-C3 alkyl, particularly R 3A and R 3B are independently selected from H and Ci- Cs-alkyl.
  • Y is S.
  • X is N.
  • a second aspect of the invention relates to a compound as described in the first aspect for use as a medicament, with the proviso that the compound includes the compounds characterized by the formula (001), (002) or (003).
  • a third aspect of the invention relates to a compound as described in the first aspect for use in treatment or prevention of cancer, with the proviso that the compound includes the compounds characterized by the formula (001), (002) or (003).
  • said cancer is selected from ependymoma, prostate cancer, esophageal cancer, thyroid cancer, hepatocellular carcinoma, testicular cancer, pediatric brain tumour, medulloblastoma, rhabdomyosarcoma, gastric cancer, pulmonary pleomorphic carcinoma, breast cancer, nonsmall cell lung cancer, liposarcoma, cervical cancer, colorectal cancer, melanoma, multiple myeloma, endometrial cancer, bladder cancer, glioblastoma, squamous cell carcinoma of the lung, ovarian cancer, head and neck cancer, and pancreatic cancer, sarcoma.
  • said cancer is selected from bladder cancer, multiple myeloma, gastric cancer, pediatric brain tumour, medulloblastoma, glioblastoma, ependymoma, and sarcoma. In certain embodiments, said cancer is selected from bladder cancer, colorectal cancer, pediatric brain tumour, medulloblastoma, multiple myeloma, and gastric cancer.
  • a fourth aspect of the invention relates to a compound as described in the first aspect use in treatment or prevention of metastasis, with the proviso that the compound includes the compounds characterized by the formula (001), (002) or (003).
  • said metastasis arises from a cancer selected from bladder cancer, colorectal cancer, pediatric brain tumour, medulloblastoma, multiple myeloma, and gastric cancer.
  • a fifth aspect of the invention relates to a compound as described in the first aspect for use as an angiogenesis antagonist, with the proviso that the compound includes the compounds characterized by the formula (001), (002) or (003).
  • a dosage form for the prevention or treatment of cancer comprising a non-agonist ligand or antisense molecule according to any of the above aspects or embodiments of the invention.
  • any specifically mentioned drug may be present as a pharmaceutically acceptable salt of said drug.
  • Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion.
  • Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate.
  • Dosage forms may be for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or as an inhalation form or suppository.
  • parenteral administration may be used, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms.
  • a pharmaceutically acceptable carrier and/or excipient may be present.
  • Topical administration is also within the scope of the advantageous uses of the invention.
  • the skilled artisan is aware of a broad range of possible recipes for providing topical formulations, as exemplified by the content of Benson and Watkinson (Eds.), Topical and Transdermal Drug Delivery: Principles and Practice (1st Edition, Wiley 2011 , ISBN-13: 978-0470450291); and Guy and Handcraft: Transdermal Drug Delivery Systems: Revised and Expanded (2 nd Ed., CRC Press 2002, ISBN-13: 978-0824708610); Osborne and Amann (Eds.): Topical Drug Delivery Formulations (1 st Ed. CRC Press 1989; ISBN-13: 978-0824781835).
  • compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the pharmaceutical composition is formulated in a way that is suitable for topical administration such as aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like, comprising the active ingredient together with one or more of solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives that are known to those skilled in the art.
  • the pharmaceutical composition can be formulated for oral administration, parenteral administration, or rectal administration.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • compositions of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892).
  • Fig. 1 Efficacy of the compound - ability to inhibit cancer cell invasion.
  • the graph represents the efficacy of E12, E15 and E15 at 3 different concentrations - 1 .M , 5 .M and 10 .M.
  • Fig. 2 Efficacy of the compound - ability to inhibit cancer cell invasion.
  • the graph represents the efficacy of E12, E15 and E25 at 10 .M.
  • Nano diffraction scanning fluorimetry nanoDSF
  • Microscale thermophoresis MST are biophysical assays used to assess the binding of the compounds to the target protein. Any temperature shift above 1.5 degree Celsius is considered as indication for significant binding.
  • FIG. 6 Effective inhibitory concentration of E25 - EC50 ( .M).
  • Fig. 7 Overview of effective inhibitory concentration of E12, E15, E25 - EC50 (
  • Fig. 9 shows the structures of the compounds E12, E15, and E25.
  • Binding site 1 is not involved in FGFR binding and located below the interaction site of FGFR’s N-terminus with FRS2.
  • Binding site 2 is the extended surface area interacting with FGFR’s C-terminal end.
  • Fig. 11 shows spheroid invasion assay using DAOY cells stimulated with bFGF +/- BGJ398 or E12 or E25 to determine the EC50 of E12 and E25.
  • Fig. 12 shows cell titer gio assay performed with DAOY cells treated with BGJ398, E12 or E25.
  • Fig. 13 shows cell titer gio assay performed with AGS cells treated with BGJ398, E12 or E25.
  • Fig. 14 shows cell titer gio assay performed with M059K cells treated with BGJ398 or E12.
  • Fig. 15 shows cell titer gio assay performed with RT 112 cells treated with BGJ398, E12 or E25.
  • Fig. 16 shows cell titer gio assay performed with DMS114 cells treated with BGJ398, E12 or E25.
  • Fig. 17 shows cell titer gio assay performed with HCT116 cells treated with BGJ398, E12 or E25.
  • Fig. 20 shows pediatric primary brain tumor cells viability after 72 h tratment in 3D culture.
  • Fig. 21 shows E12 concentration in serum.
  • Fig. 22 shows immunoblots using various FGFR-driven cell lines treated with BGJ398 or E12 showing the effect of the treatment on the downstream effectors of FGF signaling.
  • SIA Spheroid invasion assay
  • aCDc automated cell dissemination counter
  • Cell invasion is determined as the average of the distance invaded by the cells from the center of the spheroid as determined using automated cell dissemination counter (aCDc) with our cell dissemination counter software aSDIcs (Kumar et al., Sci Rep 5, 15338 (2015)) (Fig. 11).
  • Nano differential scanning fluorimetry nanoDSF
  • Purified FRS2 protein tagged with 6X Histidine residues and Guanine nucleotide-binding protein subunit beta (GB1) was diluted in the protein buffer (100mM sodium phosphate, 50mM NaCI, 0.5mM EDTA, 50mM arginine, 1mM TCEP, pH 7.0) to final concentration of 30 .M.
  • the compounds were dissolved in 100% at 50 or 100mM and further diluted to 1 mM with a final concentration of 100% DMSO.
  • Compound and protein were mixed at 1 :1 ration yielding final concentrations of 15 .M and 500 .M for the compounds.
  • the mixture was incubated at room temperature for 15 minutes before measurement. The measurement was performed on a Prometheus system in high sensitivity capillaries. Samples were subjected to a temperature gradient of 20 to 95°C with 1°C/min intervals.
  • Microscale thermophoresis MST
  • Purified FRS2 protein tagged with 6X Histidine residues and Guanine nucleotide-binding protein subunit beta (GB1) was labelled with 2 nd generation BLUE-NHS dye.
  • the protein was labelled at a final concentration of 20 .M with 60 .M dye.
  • the labelling was performed in the protein buffer without arginine supplementation.
  • Arginine was re-buffered to protein’s buffer post-labelling.
  • the compounds were dissolved in 100% at 50 or 100mM and further diluted to 1mM with a final concentration of 100% DMSO. The compounds were then diluted. In a 1 :1 serial dilution from 1mM to 61.04nM in protein buffer supplemented with 10% DMSO.
  • Radioimmunoprecipitation assay (RIPA) buffer.
  • RIPA buffer lysates were resolved by SDS- PAGE and transferred to a nitrocellulose membrane using a transfer apparatus according to the manufacturer’s instructions (Bio-Rad).
  • Membranes were probed with primary antibodies against phospho-FRS2, FRS2, ERK1/2, phospho-ERK1/2, AKT, phosphor-AKT, phospho- PKC and tubulin.
  • HRP-linked secondary antibodies (1 :5000) were used to detect the primary antibodies. Chemiluminescence detection was performed using ChemiDoc Touch Gel and Western Blot imaging system (BioRad).
  • the metabolic activity and the proliferation of the cells were determined using the Cell Titer gio assay from Promega according to the manufacturer’s instructions.
  • 250 cells/1 OOpl/per well were seeded in Greiner Bio-One p-clear 384 well plates (655090, Greiner Bio-One) and incubated overnight at 37°C.
  • the old media was then replaced with fresh serum-free media and the cells were treated with BGJ398, E12 or E25 till the desired time point.
  • 10 pl of the Cell titer gio reagent was added to each well (final concentration of cell titer gio reagent per well is 1 :10) and incubated at 37° C for 30 minutes.
  • the luminescence was then measured with a signal integration time of 0.5 to 1 second per well (Fig. 12-19).
  • Table. 1 shows the in vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) properties of E12 and E25.
  • Efflux ration represents the permeability of E12 and E25,
  • Semi-thermodynamic solubility shows the solubility of E12 and E25 in aqueous solutions.
  • Intrinsic clearance and t1/2 shows the metabolic stability of E12 and E25
  • MTT shows the toxicity of E12 and E25
  • potency shows the efficacy of E12 and E25 (Fig. 21).
  • RIPA buffer FGFR-driven cell lysates were resolved by SDS-PAGE and transferred to a nitrocellulose membrane using a transfer apparatus according to the manufacturer’s instructions (Bio-Rad). Membranes were probed with primary antibodies against phospho- FRS2, FRS2, ERK1/2, phospho-ERK1/2, AKT, phospho-AKT, phospho-PKC and tubulin. HRP-linked secondary antibodies (1:5000) were used to detect the primary antibodies.
  • Purified PTB domain of FRS2 is combined with E12 in equimolar concentrations. This complex in incubated at room temperature for 45 minutes. The interactions between the PTB domain of FRS2 and E12 is monitored and recorded using 600nm nuclear magnetic resonance spectrometer.
  • a chemical shift occurs for amino acids T159, E224, R173, A198, S179, I220, H168, R100, D138, and 1196, which all are shifted in the PTB domain of FRS2 when combined with E12.

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Abstract

L'invention concerne un composé de formule générale (100) dans laquelle Y est O ou S, X est N ou CH, L est un lieur choisi parmi la formule (I), alkyle en C1-C4, amine en C1-C3, amide en C1-C3 et amide-éther en C1-C3, Q est N ou CH, et RL est choisi parmi H et alkyle en C1-C3, et L est non substitué ou substitué par alkyle en C1-C6, -(C1-C4)-NRN1RN2, OH, CN, halogène, NRN1RN2 et/ou SO2RS, RN1, RN2, et RS étant indépendamment choisis parmi H, et alkyle en C1-C3, n vaut 0, 1, 2, 3 ou 4, chaque R1 est indépendamment choisi parmi alkyle en C1-C6, OH, ORO, COORA, CN, NO2, halogène, NRN1RN2, SO2RS, RN1, RN2, RS, RA et RO étant indépendamment choisis parmi H, et alkyle en C1-C6, ou deux R1 forment un cyclo-alkyle en C4-C8 ou un hétérocycle en C2-C8, en particulier deux R1 forment un cyclo-alkyle en C5-C6 ou un hétérocycle en C5-C6, le cyclo-alkyle ou l'hétérocycle étant non substitué ou substitué par OH, COORA, ORO CN, halogène, NRN1RN2, SO2RS, RN1, RN2, RO, RA, et RS étant indépendamment choisis parmi H, et alkyle en C1-C3, m vaut 0, 1 ou 2, et chaque R2 est indépendamment choisi parmi alkyle en C1-C3, OH, NH2, CN et halogène. Le composé est utilisé en tant que médicament, en particulier pour une utilisation dans le traitement ou la prévention du cancer.
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