Classifications

• • 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
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/40—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
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present disclosure relates to a therapeutic combination of at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor.
• the therapeutic combination disclosed herein is particularly advantageous in the treatment of KRAS G12C-mediated cancers, and more particularly in the treatment of lung, pancreatic or colorectal cancer.
• RAS proteins a family of small GTPases that integrate and transmit signals from upstream growth factor receptors, comprise the most frequently mutated protein family in human cancer and high frequency of RAS mutations are found with the top three causes of cancer deaths: lung, colorectal, and pancreatic cancer.
• RAS proteins function as a molecular switch.
• ligand stimulation results in activation of the guanine nucleotide exchange factor son of sevenless (SOS) and facilitates exchange of the inactive guanosine diphosphate (GDP)-bound state of RAS to an active guanosine triphosphate (GTP)-bound state.
• GDP inactive guanosine diphosphate
• GTP active guanosine triphosphate
• This switch between inactive and active states enables RAS to adopt a conformation that interacts with the RAS-binding domain (RBD) of its downstream effectors and facilitates the recruitment of rapidly accelerated fibrosarcoma (RAF) family members (ARAF, BRAF, CRAF) from the cytosol to the plasma membrane which eventually leads to the activation of the MAPK signaling cascade.
• Active MAPK signaling further results in the activation of gene transcription programs required for cell proliferation.
• the activation of the RAS-RAF-MAPK signaling cascade is transient and is turned off via the action of RAS-GTPase activating (GAP) proteins. These proteins activate GTPase enzymes found within RAS, which hydrolyze GTP to GDP and therefore switch RAS off.
• the KRAS G12C refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
• the assignment of amino acid codon and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P011 16: Variant p.Gly12Cys.
• the transcriptional enhanced associate domain (TEAD) family of transcription factors TEAD1 -TEAD4 are the most downstream effectors of the HIPPO- YAP1 signaling cascade, an evolutionary conserved signaling pathway whose deregulation is described for different cancer types (reviewed in Nguyen and Yi, Trends Cancer. 2019, 5:283-296).
• the core of the HIPPO pathway in mammals consists of a cascade of kinases including MST1/2 and LATS1/2, their associated adaptor proteins SAV1 and MOB1 , as well as upstream regulators, such as NF2, SCRIBBLE, CRUMBS, and multiple G protein- coupled receptors.
• HIPPO pathway kinases are mainly found in their “on” state in which they actively phosphorylate YAP1 and TAZ (WWTR1 gene) proteins. Phosphorylated YAP1 and TAZ then remain inactive through sequestration in the cytoplasm and/or degradation by the proteasomal machinery.
• HIPPO signaling is found in the “off” state, in which case cytosolic YAP1 and TAZ proteins are not anymore phosphorylated and hence free to translocate to the cell nucleus, where they associate with TEAD transcription factors.
• the YAP1 -TEAD or TAZ-TEAD couples then bind to DNA and induce the expression of genes that promote cell proliferation and cell survival (reviewed in Totaro et al., Nature Cell Bio. 2018, 20:888-899).
• Allosteric TEAD inhibitors inhibit the growth of tumor cells in vitro and in vivo and are active in tumor types that depend on TEAD activity and where activation of TEAD (YAP1 -TEAD or TAZ- TEAD) is the main driver of tumor growth.
• TEAD inhibitors In tumors, in which TEAD is not the driver of tumor cell growth, TEAD inhibitors have no effect and can be added to in vitro and in vivo models without any impact on tumor cell proliferation and survival.
• the HIPPO-YAP1 / TAZ -TEAD signaling cascade does not exist in isolation but cross-talks with other signaling pathways.
• the crosstalk between this pathway and the MAPK pathway has recently been reported (Pham et al., Cancer Discovery 2020, 11 :778-793).
• the MAPK pathway is tightly regulated by RAS proteins.
• the present disclosure provides the unexpected finding that the combination of a specific TEAD inhibitor with a KRAS G12C inhibitor is particularly effective in the treatment of tumors harboring KRAS G12C mutations, and thus for its use in the treatment of KRAS G12C-associated cancers, including lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, colon adenocarcinoma, bile duct carcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer, and ovarian cancer (Li et al., Nat Rev Cancer, 2018 Dec; 18(12):767:777).
• CMML chronic myelomonocytic leukemia
• rhabdomyosarcoma endometrial cancer
• bladder cancer bladder cancer
• ovarian cancer Li et al., Nat Rev Cancer, 2018 Dec; 18(12
• the present disclosure provides a therapeutic combination comprising at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor selected from the group consisting of molecules of formula (III), indole compounds of formula (IV), indane compounds of formula (V) as detailed hereafter and the pharmaceutically acceptable salts thereof.
• TEAD inhibitor makes it possible to stimulate/potentiate the inhibition effect of the KRAS G12C inhibitor.
• the combination of said TEAD inhibitor with said KRAS G12C inhibitor surprisingly potentiates the effect of the KRAS G12C inhibitor by several orders of magnitude and up to 100 x in some cases.
• This significant potentiation effect for the inhibition of KRAS G12C is especially even more surprisingly, given that these specific TEAD inhibitors alone are totally inactive on tumor models with KRAS G12C mutations.
• the therapeutic combination combines one or more KRAS G12C inhibitors as disclosed hereinafter and one or more TEAD inhibitors as disclosed hereinafter.
• KRAS G12C inhibitors as disclosed hereinafter and one or more TEAD inhibitors as disclosed hereinafter.
• TEAD inhibitors as disclosed hereinafter.
• halogen atom a fluorine, a chlorine, a bromine or an iodine atom
• an alkyl group a linear or branched saturated aliphatic group. More particularly, a (Cx-Cy) alkyl group, where x and y are integers, x ⁇ y, is a linear or branched saturated aliphatic group comprising from x to y carbon atoms, for example from 1 to 4 carbon atoms.
• a (Cx-Cy) alkyl group where x and y are integers, x ⁇ y, is a linear or branched saturated aliphatic group comprising from x to y carbon atoms, for example from 1 to 4 carbon atoms.
• a cycloalkyl group a cyclic alkyl group, including spiro groups. More particularly, a (C3-Cz) cycloalkyl group, where z is an integer greater than or equal to 4, is a cyclic alkyl group comprising, unless otherwise mentioned, from 3 to z carbon atoms, and being unsubstituted or substituted.
• a (C3-Cz) cycloalkyl group where z is an integer greater than or equal to 4
• z is an integer greater than or equal to 4
• a cyclic alkyl group comprising, unless otherwise mentioned, from 3 to z carbon atoms, and being unsubstituted or substituted.
• an alkenyl group a linear or branched mono- or polyunsaturated aliphatic group containing, for example, one or two ethylenic unsaturations. More particularly, a (C2-Cy) alkenyl group, where y is an integer greater than or equal to 3, is a linear or branched mono- or polyunsaturated aliphatic group containing from 2 to y carbon atoms, for example from 2 to 4 carbon atoms, and containing, for example, one or two ethylenic unsaturations.
• alkoxy group a radical -O-alkyl in which the alkyl group is as defined above. More particularly, a (Cx-Cy) alkoxy group, where x and y are integers, x ⁇ y, is an - ⁇ -(Cx- Cy) alkyl group where the (Cx-Cy) alkyl group is as previously defined.
• the alkoxy group is a (C1 -C4) alkoxy group.
• an aryl group a monocyclic or bicyclic aromatic group containing between 6 and 10 carbon atoms.
• an aryl group mention may be made of phenyl or naphthyl group;
• heteroaryl group a monocyclic or bicyclic aromatic group containing between 4 and 9 carbon atoms and containing 1 or 2 heteroatoms, selected from an oxygen atom, a nitrogen atom and a sulfur atom, more particularly selected from an oxygen atom and a nitrogen atom, still more particularly nitrogen.
• pyridinyl group and the like mention may be made of, but not limited to pyridinyl group and the like;
• a heterocyclyl or heterocyclic group a ring structure having between 3 to 12 atoms, in particular between 4 and 8 atoms, wherein one or more atoms are selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, the remainder of the ring atoms being carbon.
• a heterocyclyl or heterocyclic group may be a ring structure having, unless otherwise mentioned, between 4 and 9 carbon atoms, in particular 4 and 8, and containing 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in particular an oxygen atom and a nitrogen atom.
• the heterocyclic group may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
• the heterocyclic group is optionally substituted on carbon or nitrogen at one or more positions.
• an alkylene group a linear or branched, saturated divalent alkyl group. More particularly, a (Cx-Cy) alkylene group, where x and y are integers, x ⁇ y, is a linear or branched, saturated divalent alkyl group comprising from x to y carbon atoms.
• a (C1 -C3) alkylene group represents a linear or branched divalent carbon-based chain of 1 to 3 carbon atoms.
• an alkylthio group a radical -S-alkyl in which the alkyl group is as defined above. More particularly, a (Cx-Cy) alkylthio group, where x and y are integers, x ⁇ y, is a radical - S-(Cx-Cy) alkyl group in which the (Cx-Cy) alkyl is as defined above; for example, a (C1 - C4) alkylthio group.
• a methylthio group an ethylthio group, a propylthio group, a butylthio group, and the like;
• benzyl group a radical -CH 2 -phenyl group
• dialkylamino group an amino group substituted with two alkyl groups, in which the alkyl group is as defined above;
• alkylsulfonyl group a radical -SO2-alkyl in which the alkyl group is as defined above. More particularly, a (Cx-Cy) alkylsulfonyl group, where x and y are integers, x ⁇ y, is a radical -SO2-(Cx-Cy) alkyl group in which the (Cx-Cy) alkyl is as defined above; for example, a (C1 -C4) alkylsulfonyl group.
• methylsulfonyl group an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, and the like;
• silyl group a group containing a silicon atom.
• silyl groups includes trimethylsilyl group.
• KRAS G12C inhibitors are compounds that inhibit the KRAS G12C mutant protein.
• the KRAS G12C inhibitors used in the combination are compounds that negatively modulate or inhibit all or a portion of the enzymatic activity of KRAS G12C.
• the KRAS G12C inhibitor may be any KRAS G12C inhibitor known in the art. In particular, it is one of the KRAS G12C inhibitors described in more detail in the following paragraphs.
• the therapeutic combination described hereafter comprises one or more KRAS G12C inhibitors.
• the KRAS G12C inhibitor in one specific embodiment, may be selected from the compounds disclosed as KRAS G12C inhibitors in patent applications WO2018/217651 , WO2019/213516, WO2018/1 19183; and patent applications WO2019/99524, WO2017/201 161 and WG2020/101736.
• the KRAS G12C inhibitor may be selected from the group comprising, in particular consisting of, compounds of formula (I), in particular of formula (I’); compounds of formula (II), in particular of formula (II’), as detailed hereinafter; their pharmaceutically acceptable salts; and mixtures thereof.
• the KRAS G12C inhibitor used in the therapeutic combination is a compound of formula (I) below: wherein
• R A is hydrogen, a (C1 -C4) alkyl group or a halogen atom, in particular R A is a fluorine atom;
• R B are independently of each other a hydrogen atom or a (C1 -C4) alkyl group, in particular both R B are hydrogen atoms;
• R1 is a (C1 -C3) alkylene group, in particular a methylene group
• R2 is a (C4-C8) heterocyclyl group comprising 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in particular an oxygen atom and a nitrogen atom, and more particularly 1 or 2 nitrogen atom(s), such as a pyrrolidinyl group, unsubstituted or substituted with one or more R6;
• L1 is a bond or a (C1 -C3) alkylene group, in particular L1 is a bond;
• R3 is a (C6-C10) aryl group or a heteroaryl group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, unsubstituted or substituted with one or more R7 groups; in particular R3 is a naphthyl group substituted with one or more R7 groups; n is zero, 1 or 2, and R4 is chosen from (C1 -C4) alkyl groups unsubstituted or substituted with one or more cyano group(s) or halogen atom(s); m is zero, 1 or 2; and R5 is chosen from (C1 -C4) alkyl groups unsubstituted or substituted with one or more halogen atoms;
• R6 is a (C1 -C4) alkyl group and more particularly a methyl group
• R7 is chosen from a halogen atom, in particular a chlorine atom, and a (C1 -C4) alkyl group unsubstituted or substituted with one or more halogen atoms; or a pharmaceutically acceptable salt thereof.
• the KRAS G12C inhibitor is of formula (I’): wherein:
• R A is a halogen atom, in particular a fluorine atom
• R B are independently of each other hydrogen or a (C1 -C4) alkyl; in particular both R B are hydrogen atoms;
• R6 is as defined above and more particularly a methyl group
• R7 is a halogen atom, in particular a chlorine atom; or a pharmaceutically acceptable salt thereof.
• the KRAS G12C inhibitor used in the therapeutic combination is 2-((S)-4-(7-(8-chloronaphthalen-1 -yl)-2-(((S)-1 -methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2- yl)aceton itrile, in other words the compound of formula: which corresponds to Adagrasib proposed by Mirati Therapeutics, Inc., also known as MRTX849.
• the KRAS G12C inhibitor used in the therapeutic combination is of formula (II) below: wherein:
• R8 is a hydrogen atom, a halogen atom, for example a fluorine atom, or a (C1 -C3) alkyl group unsubstituted or substituted with one or more halogen atoms, in particular with one or more fluorine atoms; in particular R8 is a hydrogen atom;
• R9 is a halogen atom, in particular a fluorine atom or a (C1 -C3) alkyl group unsubstituted or substituted with one or more halogen atoms, in particular with one or more fluorine atoms; in particular R9 is a fluorine atom;
• L2 is a single bond or a methylene group; in particular a single bond;
• R10 is a (C6-C10) aryl group or a heteroaryl group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, in particular a phenyl group, unsubstituted or substituted with one or more R13 groups;
• R1 1 is a (C6-C10) aryl group or a heteroaryl group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, unsubstituted or substituted, preferably in ortho positions, with one or more R14 groups;
• R c is a hydrogen atom or a (C1 -C3) alkyl group
• R D is a hydrogen atom, a (C1 -C3) alkyl group or a halogen atom in particular a fluorine atom; p is zero, 1 or 2; and R12 is a (C1 -C3) alkyl group, in particular a methyl group;
• R13 is chosen from a halogen atom, in particular a fluorine atom, a hydroxyl group (OH) and a (C1 -C3) alkoxy group;
• R14 is chosen from a hydrogen atom, a (C1 -C4) alkyl group and a (C3-C6) cycloalkyl group; or a pharmaceutically acceptable salt thereof.
• R10 is the following group:
• R11 is a group: in particular a group
• the KRAS G12C inhibitor is of formula (II’) below: wherein:
• R c and R D are as defined above, in particular both R c and R D are hydrogen atoms,
• R8 is as defined above, in particular R8 is a hydrogen atom
• R9 is as defined above, in particular a halogen atom and more particularly a fluorine atom
• R12 is as defined above, in particular a methyl group
• R13 are as defined above, in particular one is a hydroxyl group and the other a fluorine atom,
• R14 are as defined above, in particular (C1 -C3) alkyl groups; and more particularly one is a methyl group and the other an isopropyl group, or a pharmaceutically acceptable salt thereof.
• the KRAS G12C inhibitor used in the therapeutic combination is 4-((S)-4-acryloyl-2-methylpiperazin-1 -yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-1 -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1 H)-one, in other words the compound of formula: which corresponds to Sotorasib proposed by Amgen, also known as AMG 510.
• the KRAS G12C inhibitor used in the therapeutic combination is: 2-((S)-4-(7-(8-chloronaphthalen-1 -yl)-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1 -(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Adagrasib, also known as MRTX849);
• Adagrasib (MRTX849) is the KRAS G12C used in the therapeutic combination.
• Sotorasib (AMG-510) is the KRAS G12C used in the therapeutic combination.
• TEAD inhibitors are compounds that have an inhibitory activity of YAP1/TAZ-TEAD or TEAD-dependent gene transcription.
• the therapeutic combination described hereinafter comprises one or more specific TEAD inhibitors as disclosed hereafter.
• the TEAD inhibitor used in the therapeutic combination of the present disclosure is selected from the group comprising, in particular consisting of, molecules of formula (III), indole compounds of formula (IV), indane compounds of formula (V), as detailed hereinafter, their pharmaceutically acceptable salts, and mixtures thereof.
• the TEAD inhibitor used in the therapeutic combination is of formula (III) below wherein X1 is a halogen atom, in particular a chlorine atom;
• X2 is a (C1 -C4) alkyl group, in particular a methyl group; or a pharmaceutically acceptable salt thereof.
• N-(3-(4-chlorophenoxy)-4- methylphenyl)acrylamide also known as K-975.
• the TEAD inhibitor used in the therapeutic combination is selected from the indole compounds disclosed in the patent application WO2021/204823.
• the TEAD inhibitor is of formula (IV) below wherein q is an integer chosen from 0 and 1 ;
• G1 is chosen from:
• G2 is chosen from:
• G3 is chosen from:
• G4 is chosen from a hydrogen atom and a (C1 -C4) alkyl group
• G5 is chosen from a fluorine atom and a trifluoromethyl group
• G6 is chosen from:
• G7 is chosen from:
• (C1 -C4) alkyl group in particular a methyl group, unsubstituted or substituted with a (C1 -C3) alkoxy group, in particular a methoxy group, or a hydroxy group,
• G8 is chosen from a hydrogen atom and a (C1 -C4) alkyl group unsubstituted or substituted with a di(C1 -C4) alkylamino group,
• G9 and G10 are identical or different and chosen from (C1 -C3) alkyl group unsubstituted or substituted with one or more fluorine atoms,
• G11 is chosen from a hydrogen atom, a fluorine atom and a chlorine atom; or a pharmaceutically acceptable salt thereof.
• the TEAD inhibitor is of formula (IV’) below wherein G1 , G2, G4, G7, G8 and G1 1 are as defined above.
• TEAD inhibitors of formula (IV) or (IV’) mention may be made of the compounds for which G4 is a hydrogen atom.
• TEAD inhibitors of formula (IV) or (IV’) mention may be made of the compounds for which G7 is a hydrogen atom or a (C1 -C4) alkyl group, especially a methyl group, unsubstituted or substituted with a (C1 -C3) alkoxy group, especially a methoxy group.
• TEAD inhibitors of formula (IV) or (IV’) mention may be made of the compounds for which G8 is a hydrogen atom.
• TEAD inhibitors of formula (IV) or (IV’) mention may be made of the compounds for which G11 is a hydrogen atom.
• TEAD inhibitors of formula (IV) mention may be made of the compounds for which: q is 0,
• G1 is a single bond or a methylene group
• G2 is chosen from:
• G2 is a phenyl group substituted with one or more G3 groups, G3 being in particular a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group.
• the TEAD inhibitor is of formula (IV), in which: q is 0,
• G1 is a single bond or a methylene group
• G2 is chosen from a phenyl group unsubstituted or substituted with one or more G3 groups, G3 a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group;
• G4 is a hydrogen atom
• G7 is a hydrogen atom or a (C1 -C4) alkyl group, especially a methyl group, unsubstituted or substituted with a (C1 -C3) alkoxy group, especially a methoxy group;
• G8 is a hydrogen atom
• G11 is a hydrogen atom; or a pharmaceutically acceptable salt thereof.
• TEAD inhibitors of formula (IV) mention may be made in particular of the following compounds:
• TEAD inhibitors of formula (IV) may be prepared according to the processes as disclosed in the above-referenced patent application WO2021/204823.
• the TEAD inhibitor used in the therapeutic combination is selected from the indane compounds disclosed the patent application W02022/023460 filed by SANOFI.
• the TEAD inhibitor is of formula (V) wherein:
• F1 is chosen from:
• F8 is a (C1 -C4) alkyl group, in particular a methyl group
• F2 is chosen from:
• (C4-C8) cycloalkyl group in particular a cyclohexyl group or a cyclopentyl group and more particularly a cyclohexyl group, said (C4-C8) cycloalkyl group being unsubstituted or substituted with one or more F5 groups;
• heteroaryl group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms selected from an oxygen atom and a nitrogen atom, in particular a pyridinyl group, said heteroaryl group being unsubstituted or substituted with one or more F5 groups;
• (C1 -C6) alkyl group in particular a (C1 -C4) alkyl group, said (C1 -C6) alkyl group being substituted with one or more fluorine atoms;
• F3 is chosen from:
• F4 is chosen from: - a halogen atom, in particular a fluorine atom or a chlorine atom;
• F5 is chosen from:
• halogen atom in particular a fluorine atom
• F6 is chosen from a hydrogen atom and a halogen atom, in particular a fluorine atom;
• F7 is independently chosen from:
• halogen atom in particular a fluorine atom
• the TEAD inhibitor is of formula (V’) wherein: F1 is chosen from:
• F2 is chosen from:
• (C4-C8) cycloalkyl group in particular a cyclohexyl group, said (C4-C8) cycloalkyl group being unsubstituted or substituted with one or more F5 groups;
• heteroaryl group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms selected from an oxygen atom and a nitrogen atom, in particular a pyridinyl group, said heteroaryl group being unsubstituted or substituted with one or more F5 groups;
• (C1 -C4) alkyl group substituted with one or more fluorine atoms in particular a (C2-C4) alkyl group substituted with one or more fluorine atoms, more particularly a (C2-C3) alkyl group substituted with a trifluoromethyl group;
• F3 is chosen from:
• F4 is chosen from:
• halogen atom in particular a fluorine atom
• F5 is chosen from:
• halogen atom in particular a fluorine atom
• the TEAD inhibitor is of formula (V) in which the indane is substituted with the radical -F1 -F2 in position 1 according to the IUPAC numbering, in other words is a compound of the following formula (Va): or a pharmaceutically acceptable salt thereof, wherein F1 , F2, F3, F6, F7 and s are as defined in the present disclosure.
• the TEAD inhibitor is of formula (V’) in which the indane is substituted with the radical -F1-F2 in position 1 according to the IUPAC numbering, in other words is a compound of the following formula (V’a): or a pharmaceutically acceptable salt thereof, wherein F1 , F2, and F3 are as defined in the present disclosure.
• the TEAD inhibitor is of formula (V) in which the indane is substituted with the radical -F1 -F2 in position 3 according to the IUPAC numbering, in other words is a compound of the following formula (Vb): or a pharmaceutically acceptable salt thereof, wherein F1 , F2, F3, F6, F7 and s are as defined in the present disclosure.
• the TEAD inhibitor is of formula (V’) in which the indane is substituted with the radical -F1 -F2 in position 3 according to the IUPAC numbering, in other words is a compound of the following formula (V’b): or a pharmaceutically acceptable salt thereof, wherein F1 , F2, and F3 are as defined in the present disclosure.
• the TEAD inhibitor is of formula (V), in particular of formula (V’), or of any sub-formula (Va), (Vb), (V’a) or (V’b) thereof, in which F3 is a hydrogen atom.
• the TEAD is of formula (V), in particular of formula (V’), or of any sub-formula (Va), (Vb), (V’a) or (V’b) thereof, in which:
• F1 is an oxygen atom and F2 is chosen from:
• cycloalkyl group in particular a cyclohexyl group or a cyclopentyl group, said cycloalkyl group being unsubstituted or substituted with one or more F5 groups;
• the TEAD inhibitor is of formula (V), in particular of formula (V’), or of any sub-formula (Va), (Vb), (V’a) or (V’b) thereof, in which F2 is chosen from:
• cycloalkyl group in particular a cyclohexyl group, said cycloalkyl group being unsubstituted or substituted with one or more F5 groups, provided that F1 is an oxygen atom.
• TEAD inhibitors of formula (V), in particular of formula (V’), or of any sub-formula (Va), (Vb), (V’a) or (V’b) thereof mention may be made in particular of the compounds for which:
• - F2 is a (C4-C8) cycloalkyl group, in particular a cyclohexyl group, substituted with on or more F5 groups, in particular said F5 groups being chosen from a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group.
• TEAD inhibitors of formula (V), in particular of formula (V’), or of any sub-formula (Va), (Vb), (V’a) or (V’b) thereof mention may be made in particular of the compounds for which
• F1 is a -N(H)- group
• - F2 is a phenyl group substituted with one or more F4 groups, in particular said F4 groups being chosen from a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group, or a halogen atom, in particular a fluorine atom.
• the F4 group(s) is(are) in the meta and/or para position(s) of the F2 phenyl group.
• the F5 group(s) is(are) in the para and/or meta position(s), in particular in the para position of the F2 group.
• the TEAD inhibitor is of formula (V’), in particular of formula (V’a) and (V’b), for which: F1 is chosen from an oxygen atom and a group -N(H)-;
• F2 is chosen from:
• F3 is chosen from a hydrogen atom and a methyl group
• F4 is chosen from a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group and a -C(O)-O-methyl group;
• F5 is chosen from a fluorine atom and a trifluoromethyl group; or a pharmaceutically acceptable salt thereof.
• the TEAD inhibitor is of formula (V), in particular of formula (Va) or (Vb), for which:
• F1 is an oxygen atom or a group -N(H)-;
• F2 is chosen from:
• (C4-C8) cycloalkyl group in particular a cyclohexyl group, said (C4-C8) cycloalkyl group being unsubstituted or substituted with one or more F5 groups;
• F3 is a hydrogen atom or a methyl group; in particular F3 is a hydrogen atom;
• F4 is a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group, or a halogen atom, in particular a fluorine atom;
• F5 is a (C1 -C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group;
• F6 is a hydrogen atom; and s is 0; or a pharmaceutically acceptable salt thereof.
• TEAD inhibitors of formula (V) mention may be made in particular of the following compounds:
• TEAD inhibitors of formula (V) may be prepared according to the processes as disclosed in the above-referenced patent application W02022/023460.
• the therapeutic combination uses as the TEAD inhibitor: N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide, also known as K-975;
• N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1 H-inden-5-yl)acrylamide or a pharmaceutically acceptable salt thereof.
• the compounds of formula (I), (II), (III), (IV) and (V), or of any sub-formula thereof, as described above may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers and also mixtures thereof.
• the compounds of formula (I), (II), (III), (IV) and (V), or of any sub-formula thereof, may exist in the form of bases or addition salts with acids or bases, in particular pharmaceutically acceptable salts.
• the combination may comprise one or more KRAS G12C inhibitors selected from the group comprising, in particular consisting of, compounds of formula (I), compounds of formula (II), compounds of any sub-formula thereof, and pharmaceutically acceptable salts thereof as defined above; and one or more specific TEAD inhibitors selected from the group comprising, in particular consisting of, compounds of formula (III), compounds of formula (IV), compounds of formula (V), compounds of any sub-formula thereof, and pharmaceutically acceptable salts thereof as defined above.
• KRAS G12C inhibitors selected from the group comprising, in particular consisting of, compounds of formula (I), compounds of formula (II), compounds of any sub-formula thereof, and pharmaceutically acceptable salts thereof as defined above.
• the combination may comprise: one or more of KRAS G12C inhibitors chosen from:
• N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide also known as K-975;
• N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1 H-inden-5-yl)acrylamide or a pharmaceutically acceptable salt thereof.
• the inventors have shown that the presence of a specific TEAD inhibitor as described above, in combination with a KRAS G12C inhibitor, makes it possible to drastically enhance the efficiency of the KRAS G12C inhibitor.
• the combination of a TEAD inhibitor as disclosed hereabove and a KRAS G12C inhibitor results in synergistically effect for inhibiting KRAS G12C protein.
• the potentiation effect of the addition of said TEAD inhibitor in combination with a KRAS G12C inhibitor advantageously allows to consider the implementation of a reduced dose of the KRAS G12C inhibitor with the same, or even an improved efficacy.
• KRAS G12C inhibitor and said TEAD inhibitor are thus used in combination therapy.
• the therapeutic combination of said KRAS G12C inhibitor(s) and said TEAD inhibitor(s) is more particularly for use in treating pathologies involving KRAS G12C, in particular in treating KRAS G12C-associated diseases or disorders, especially KRAS G12C-mediated cancers.
• the KRAS G12C-mediated cancers include lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, colon adenocarcinoma, bile duct carcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer, and ovarian cancer.
• CMML chronic myelomonocytic leukemia
• rhabdomyosarcoma endometrial cancer
• bladder cancer bladder cancer
• ovarian cancer ovarian cancer.
• KRAS G12C inhibitor and said TEAD inhibitor may advantageously be used in the treatment of non-small cell lung, small cell lung, pancreatic or colorectal cancer.
• KRAS G12C inhibitor(s) and specific TEAD inhibitor(s) as disclosed above for use in the treatment of KRAS G12C-mediated cancers, in particular lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, colon adenocarcinoma, bile duct carcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer, and ovarian cancer; and more particularly of non-small cell lung, small cell lung, pancreatic or colorectal cancer.
• CMML chronic myelomonocytic leukemia
• the therapeutic combination may be used in the treatment of a patient who has exhibited resistance to prior anti-cancer therapy.
• the KRAS G12C inhibitor(s) and TEAD inhibitor(s) used in combination can be administered simultaneously or separately.
• the administration of a therapeutic combination can thus include simultaneous administration of the two inhibitors in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.
• the KRAS G12C inhibitor is more particularly administered in a therapeutically effective amount.
• a “therapeutically effective amount or dose” is an amount that is sufficient to negatively modulate or inhibit the activity of KRAS G12C, and thus to ameliorate, or in some manner reduce a symptom or stop or reverse progression of the condition involving KRAS G12C.
• a therapeutically effective amount may vary depending upon the subject (e.g. the weight, age and gender of the subject), disease conditions being treated, the severity of the disease condition and the manner of administration.
• the TEAD inhibitor is co-administered in combination with the KRAS G12C inhibitor in an amount sufficient to achieve the effect of potentiation of the activity of said KRAS G12C inhibitor.
• the TEAD inhibitor in combination therapy is not administered in a therapeutically effective amount. This means that the TEAD inhibitor alone has no effect in the therapeutic treatment, in particular for the treatment of the targeted cancer.
• co-administration encompass administration of both KRAS G12C inhibitor(s) and TEAD inhibitor(s) to a subject so that both inhibitors and/or their metabolites are present in the subject at the same time.
• Co-administration includes combination and pharmaceutical composition not exclusively limited to the ones which are obtained by physical association of the constituents in a single unit dosage, but also to those which allow a separate administration, which can be simultaneous or sequential (also called “spaced out” or “spread out”) over a period of time. Simultaneous administration in separate compositions and administration in a single unit dosage are preferred.
• the KRAS G12C inhibitor and TEAD inhibitor of the therapeutic combination may be administered by any method well known in the art. They may be administered by any route, including, without limitation, parenteral, oral, transdermal, and other dosage forms.
• the therapeutic combination may also be administered in combination with at least one third active agent, in particular selected from known active agents in anti-cancer therapy.
• the therapeutic combination or pharmaceutical composition may also be used in combination with other treatments, such as radiotherapy or chemotherapy.
• both KRAS G12C inhibitor(s) and TEAD inhibitor(s), in particular as described above can be formulated together in the same dosage form and administered simultaneously.
• KRAS G12C inhibitor(s) and TEAD inhibitor(s) may be used as medicaments, especially medicaments for the treatment of KRAS-G12C-mediated cancers.
• a medicament that comprise at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor as disclosed hereabove.
• the present disclosure relates to a pharmaceutical composition
• a pharmaceutical composition comprising the previously described therapeutic combination, in other words comprising at least one KRAS G12C inhibitor in particular as described above and at least one TEAD inhibitor as disclosed hereabove.
• the pharmaceutical composition contains a therapeutically effective dose of said KRAS G12C inhibitor and said TEAD inhibitor in an effective amount to reach a potentiation effect for inhibiting KRAS G12C protein.
• said pharmaceutical composition is for use in the treatment of KRAS G12C-mediated cancers as mentioned above.
• the pharmaceutical composition may also contain at least one pharmaceutically acceptable excipient, diluent and/or carrier.
• excipients, diluents and/or carriers are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients, diluents and carriers known to those skilled in the art.
• the KRAS G12C inhibitor(s) and TEAD inhibitor(s) as described above can be simultaneously administered, wherein both the inhibitors are present in separate formulations.
• the KRAS G12C inhibitor(s) and the TEAD inhibitor(s) can be administered separately, for example the KRAS G12C inhibitor can be administered just followed by the TEAD inhibitor, or vice versa.
• the KRAS G12C inhibitor and the TEAD inhibitor are administered a few minutes apart, or a few hours apart, or a few days apart.
• the KRAS G12C inhibitor and the TEAD inhibitor when simultaneously administered in separate dosage forms or separately administered can be comprised in distinct pharmaceutical compositions.
• Said compositions may contain at least one pharmaceutically acceptable excipient, diluent and/or carrier as described above.
• the present disclosure relates to a kit comprising in one or more separate packages the previously described therapeutic combination or a pharmaceutical composition comprising both KRAS G12C inhibitor(s) and TEAD inhibitor(s) as disclosed hereabove, optionally together with instructions for administration thereof and/or with a medical device for administration.
• the kit is for use in co-administration of said KRAS G12C inhibitor and said TEAD inhibitor, either simultaneously or separately, especially for the treatment of KRAS G12C-mediated cancer, in particular of lung, colorectal or pancreatic cancer.
• the KRAS G12C inhibitor(s) and the TEAD inhibitor(s) can be contained in a single pharmaceutical composition or in two separate pharmaceutical compositions in the kit.
• a method for treating a KRAS G12C- associated cancer comprising administering the previously described therapeutic combination or pharmaceutical composition to a patient in need thereof.
• Also provided herein is a use of a therapeutic combination as disclosed herein in the manufacture of a medicament for the treatment of KRAS G12C-mediated cancers.
• TEAD inhibitors and KRAS G12C inhibitors used in the examples described hereinafter are the following ones.
• TEAD inhibitor N°1 Commercial TEAD K-975;
• TEAD inhibitor N°2 N-(1 -((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1 H-inden-5- yl)acrylamide;
• TEAD inhibitor N°3 N-(1 -(4-(trifluoromethyl)phenyl)-1 H-indol-5-yl)acrylamide;
• TEAD inhibitor N°4 N-(3-(methoxymethyl)-1 -(4-(trifluoromethyl)phenyl)-1 H-indol-5- yl)acrylamide;
• TEAD inhibitor N°5 N-(3-methyl-1 -(3-(trifluoromethyl)benzyl)-1 H-indol-5-yl)acrylamide
• TEAD inhibitor N°6 N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1 H-inden- 5-yl)acrylamide
• TEAD inhibitor N°7 N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1 H-inden-5- yl)acrylamide;
• TEAD inhibitor N°8 N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1 H-inden-5- yl)acrylamide.
• TEAD inhibitors N°3, N°4 and N°5 were prepared according to the detailed synthesis described in the PCT patent application WO2021/204823.
• TEAD inhibitors N°2, N°6, N°7 and N°8 were prepared according to the detailed synthesis described in the PCT patent application W02022/023460.
• KRAS G12C inhibitor N°1 Adagrasib MRTX849 of Mirati Therapeutics, Inc.;
• KRAS G12C inhibitor N°2 Sotorasib AMG 510 of Amgen.
• Example 1 Rav design combination experiment in KRAS mutant HOP-62 cell line using the KRAS G12C inhibitor N°1 and TEAD inhibitors N°1 and N°2
• the NSCLC cell line HOP62 which carries a KRASG12C mutation was used for this study.
• HO-P62 cells were seeded in 384 well plates at 300 cells per well and incubated 24 hours at 37°C and 5% CO2.
• the KRAS G12C inhibitor N°1 used at 14 concentrations ranging from 10,000 nM to 0.006 nM was combined with TEAD inhibitors used at 18 concentrations ranging from 10,000 nM to 0.0001 nM, added to HOP-62 cells and incubated for 96 hours at 37°C and 5% CO2.
• Compound dilution and distribution to cells was performed on the TECAN MCA384 robotic platform.
• Cell proliferation was measured using Cell Titer Gio from PROMEGA (luminescence).
• Example 2 Ray design combination experiment in KRAS mutant H-2030 cell lines using the KRAS G12C inhibitor N°1 and TEAD inhibitors N°1 and N°2
• the NSCLC cell line H-2030 which carries a KRASG12C mutation was used for this study.
• H-2030 cells were seeded in 384 well plates at 250 cells per well and incubated 24 hours at 37°C and 5% CO2.
• the KRAS G12C inhibitor N°1 used at 14 concentrations ranging from 10,000 nM to 0.006 nM was combined with TEAD inhibitors used at 18 concentrations ranging from 10,000 nM to 0.0001 nM, added to H-2030 cells and incubated for 144 hours at 37°C and 5% CO2.
• Compound dilution and distribution to cells was performed on the TECAN MCA384 robotic platform.
• Cell proliferation was measured using Cell Titer Gio from PROMEGA (luminescence).
• IC 50 ai IC 50 of active compound with inactive compound at one concentration
• IC 50 a IC 50 of active compound alone at one concentration
• Example 3 IC50 shift experiment in the KRAS G12C mutant NSCLC cell line HOP-62 using the KRAS G12C inhibitors N°1 and N°2 and a set of structurally different TEAD inhibitors.
• the KRAS G12C mutant NSCLC cell line HOP-62 was used for this study. Cells were seeded in 96 well plates at 1250 cells per well and incubated 24 hours at 37°C and 5% CO2. The KRAS G12C inhibitors N°1 and N°2 were used at 10 concentrations and combined with TEAD inhibitors used at 2 concentrations. Compound dilution and distribution to cells was performed on the TECAN MCA384 robotic platform. Cells were incubated with inhibitors for 144 hours at 37°C and 5% CO2. Cell proliferation was measured using Cell Titer Gio from PROMEGA (luminescence). For each KRAS G12C inhibitor, IC50 values in these cell lines were determined in the absence or presence of TEAD inhibitors.
• the different TEAD inhibitors potentiate the IC50s of the KRAS G12C inhibitor N°1 or N°2 by up to 21 -fold in HOP-62 KRAS G12C mutant NSCLC cells.

Landscapes

• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

Family

ID=81326107

Family Applications (1)

Country Status (5)

Cited By (2)

Citations (11)

• 2023
  • 2023-04-03 EP EP23713397.0A patent/EP4504203A1/en active Pending
  • 2023-04-03 CN CN202380032305.8A patent/CN118973584A/zh active Pending
  • 2023-04-03 JP JP2024557983A patent/JP2025511161A/ja active Pending
  • 2023-04-03 WO PCT/EP2023/058693 patent/WO2023194310A1/en not_active Ceased
  • 2023-04-03 US US18/852,884 patent/US20250295664A1/en active Pending

Patent Citations (12)

Non-Patent Citations (10)

Also Published As

Similar Documents

Legal Events