WO2024133721A1 - Combinaisons d'un inhibiteur de ctps1 et d'un inhibiteur d'iap pour une utilisation dans le traitement du cancer - Google Patents

Combinaisons d'un inhibiteur de ctps1 et d'un inhibiteur d'iap pour une utilisation dans le traitement du cancer Download PDF

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WO2024133721A1
WO2024133721A1 PCT/EP2023/087318 EP2023087318W WO2024133721A1 WO 2024133721 A1 WO2024133721 A1 WO 2024133721A1 EP 2023087318 W EP2023087318 W EP 2023087318W WO 2024133721 A1 WO2024133721 A1 WO 2024133721A1
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Prior art keywords
inhibitor
cyclopropanesulfonamido
ctps1
thiazol
iap
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PCT/EP2023/087318
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English (en)
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Andrew Parker
Philip BEER
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Step Pharma S.A.S.
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Publication of WO2024133721A1 publication Critical patent/WO2024133721A1/fr

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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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to combinations, in particular the combination of a CTPS1 inhibitor and an IAP inhibitor, pharmaceutical compositions and kits comprising such combinations which may be of use in the treatment of cancer and to related aspects.
  • Cancer can affect multiple cell types and tissues but the underlying cause is a breakdown in the control of cell division. This process is highly complex, requiring careful coordination of multiple pathways, many of which remain to be fully characterised.
  • Cell division requires the effective replication of the cell’s DNA and other constituents. Interfering with a cell’s ability to replicate by targeting nucleic acid synthesis has been a core approach in cancer therapy for many years. Examples of therapies acting in this way are 6-thioguanine, 6-mecaptopurine, 5- fluorouracil, cytarabine, gemcitabine and pemetrexed.
  • Cancer therapeutics against a wide array of specific targets are available.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • CTPS cytidine triphosphate synthase
  • CTPS1 and CTPS2 Whilst cancer cells are dependent on CTPS activity in order to proliferate, the precise role that CTPS1 and CTPS2 play in cancer is currently not completely clear.
  • CTPS inhibitors that inhibit both CTPS1 and CTPS2 have been developed for oncology indications up to phase l/ll clinical trials, but were stopped due to toxicity and efficacy issues.
  • nucleoside-analogue prodrugs (3-deazauridine (DAU), CPEC, carbodine) which are converted to the active triphosphorylated metabolite by the kinases involved in pyrimidine biosynthesis: uridine/cytidine kinase, nucleoside monophosphate-kinase (NMP-kinase) and nucleoside diphosphatekinase (NDP-kinase).
  • NMP-kinase nucleoside monophosphate-kinase
  • NDP-kinase nucleoside diphosphatekinase
  • the remaining inhibitors (acivicin, DON) are reactive analogues of glutamine, which irreversibly inhibit the glutaminase domain of CTPS.
  • none of the inhibitors of CTPS developed to date are selective for one isoform of CTPS over the other.
  • IAP proteins are a family of proteins that are able to inhibit apoptosis through multiple mechanisms. Many cancers use evasion of apoptosis to enhance survival and proliferation. IAP proteins are frequently over-expressed in human cancers, creating an apoptosis-resistant state (Cetraro 2022). Inhibitors of IAP proteins have been developed as potential therapies for cancer. Most of these drugs attempt to mimic the activity of second mitochondrial-derived activator of caspases (SMAC) which is a natural antagonist of IAP activity.
  • SMAC second mitochondrial-derived activator of caspases
  • IAP inhibitors This class of drug are, therefore, often interchangeably referred to as IAP inhibitors or SMAC mimetics.
  • IAP inhibitors including birinapant, have been tested in early phase clinical trials recruiting patients with haematological and solid tumours; whilst clinical responses have been reported, overall efficacy has been relatively modest (Cetraro 2022).
  • cancer therapies may demonstrate high in vivo efficacy, reduction in the dose required for effect in vivo, an improved safety profile/reduced side effects, or the like.
  • Summary of the invention The invention provides a CTPS1 inhibitor for use in the treatment of cancer with a IAP inhibitor.
  • the invention provides a IAP inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.
  • the invention provides a CTPS1 inhibitor and a IAP inhibitor for use in the treatment of cancer.
  • the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a IAP inhibitor.
  • the invention provides the use of a IAP inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.
  • the invention provides the use of a CTPS1 inhibitor and a IAP inhibitor in the manufacture of a medicament for the treatment of cancer.
  • the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and a IAP inhibitor.
  • the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and a IAP inhibitor.
  • the invention provides a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising a IAP inhibitor.
  • a CTPS1 inhibitor is an agent which directly inhibits the enzymatic activity of the CTPS1 enzyme through interaction with the enzyme. Direct inhibition of the CTPS1 enzyme may be quantified using any suitable assay procedure, though is suitably performed using the procedure set out in Example 1.
  • CTPS1 inhibitors may demonstrate an IC 50 of 10 uM or lower, such as 1uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme.
  • CTPS1 inhibitors of particular interest are those demonstrating an IC 50 of 10 uM or lower, such as 1uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme using the assay procedure set out in Example 1.
  • CTPS1 inhibitors may demonstrate a selectivity for CTPS1 over CTPS2.
  • the inhibitors demonstrate a selectivity of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular at least 1000-fold.
  • CTPS1 inhibitors of particular interest are those demonstrating a selectivity for CTPS1 over CTPS2, suitably of at least 2-fold, such as at least 30-fold, especially at least 60-fold and in particular at least 1000-fold using the assay procedure set out in Example 2.
  • the selectivity is for human CTPS1 over human CTPS2.
  • CTPS1 inhibition and CTPS1 vs CTPS2 selectivity should be based on human forms of the enzymes.
  • CTPS1 inhibitor may be selected from the following compounds: A compound of formula (I): wherein R 1 is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R3 is H, CH3, halo, OC1-2alkyl or CF3; R4 and R5 are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3- 6 cycloalkyl or C 3-6 heterocycloalkyl ring; R 6 is H or C 1-3 alkyl; Ar1 is a 6-membered aryl or heteroaryl
  • CTPS1 inhibitor is selected from the following (‘List A’) compounds: N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-5-phenylpicolinamide; N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyridin-3-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3- yl)benzamide (R enantiomer); N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(tri
  • CTPS1 inhibitors are disclosed in PCT publication number WO2019106146 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 110 of WO2019106146 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound R1 to R93 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor is compound of formula (II): wherein R 1 is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R3 is H, halo, CH3, OC1-2alkyl or CF3; or R3 together with R5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4 and R 5 are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0- 2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, C 1-3 alkyleneOC 1- 3 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl,
  • CTPS1 inhibitor is selected from the following (‘List B’) compounds: N-([1,1'-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-2- yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridi)
  • CTPS1 inhibitors are disclosed in PCT publication number WO2019106156, which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 118 of WO2019106156, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound T1 to T465 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor is selected from the following (‘List C’) compounds: N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)cyclopentanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2- methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)pyridin-3- yl)phenyl)propanamide; 2-methyl-N-(2-
  • CTPS1 inhibitors are disclosed in PCT publication number WO2019179652 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 148 of WO2019179652 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound P1 to P225 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • Such CTPS1 inhibitors are also disclosed in PCT publication number WO2019180244 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 148 of WO2019180244 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound P1 to P225 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • compounds or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof in PCT publication number WO2019180244 which are selective for CTPS1 over CTPS2 (e.g. human CTPS1 over human CTPS2), such as those identified in Table 19.
  • CTPS1 e.g. human CTPS1 over human CTPS2
  • the CTPS1 inhibitor is a compound of formula (IV): wherein: (a) when R 4 , R 5 , X, Y and R 1 are as follows: then W is N, CH or CF; (b) when R 4 , R 5 , X, W and R 1 are as follows: then Y is CH or N; (c) when W, X, Y and R1 are as follows: then R 4 and R 5 are joined to form the following structures: (d) when W, R 4 , R 5 , X and Y are as follows: then R 1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • formula (IV) wherein: (a) when R 4 , R 5 , X, Y and R 1 are as follows: then W is N, CH or CF; (b) when R 4 , R 5 , X, W and R 1 are as follows: then Y
  • CTPS1 inhibitor is selected from the following (‘List D’) compounds: (R)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; (S)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-eth)-N
  • CTPS1 inhibitors are disclosed in PCT publication number WO2020083975 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound selected from P112, P113, P114, P115, P136, P137, P139, P143, P145, P165, P166, P186, P197, P206 and P207 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • compounds or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof in PCT publication number WO2020083975 which are selective for CTPS1 over CTPS2 (e.g. human CTPS1 over human CTPS2), such as those identified in Table 11.
  • the CTPS1 inhibitor is a compound of formula (V): (a) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: , then R4 and R5 together with the carbon atom to which they attached form: , then R4 and R5 together with the carbon atom to which they are attached form: , then (e) when A, X, Y, Z, R1, R4 and R5 are as follows: t (f) when A, V, W, R1, R4, R5, R10 and R12 are as follows: , (g) when A, V, W, R1, R4, R5, R10 and R12 are as follows: , (h) when A, V, W, R 1 , R 4 , R 5 , R 10 and R 12 are as follows or a pharmaceutically acceptable salt
  • CTPS1 inhibitor is selected from the following (‘List E’) compounds: N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)cyclohexane-1-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-(methylsulfonamido)pyrimidin-4-yl)cyclohexane-1- carboxamide; 1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)
  • CTPS1 inhibitors are disclosed in PCT publication number WO2020245664 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound selected from P319, P231 to P234, P236, P237, P238, P239, P240, P241, P243, P245, P246, P247, P249, P250, P252, P253, P257, P259, P262, P263 and P140 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor is selected from the following (‘List F’) compounds: 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5
  • CTPS1 inhibitors are disclosed in PCT publication number WO2020245665 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 204 of WO2020245665 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound selected from P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260, P261, P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318 or a pharmaceutically acceptable salt and
  • CTPS1 inhibitor is selected from the following (‘List G’) compounds: 4-(2-((2,2-difluoroethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; and 2-(2-((2,2-difluoroethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2- fluorobutanamide; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitors are disclosed in PCT publication number WO2021053403 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 191 of WO2021053403 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound selected from P271 and P284 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor is selected from the following (‘List H’) compounds: 4-(2-((1-cyanocyclopropane)-1-sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide; and 4-(2-((cyanomethyl)sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide; or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • (‘List H’) compounds 4-(2-((1-cyanocyclopropane)-1-sulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)t
  • CTPS1 inhibitors are disclosed in PCT publication number WO2021053402 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of clauses 1 to 191 of WO2021053402 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, in particular a compound selected from P285 and P287 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor may be 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as ‘CTPS-IA’): or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS-IA is a potent and selective inhibitor of CTPS1 (see e.g. WO2020083975).
  • CTPS1 inhibitor may be N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2- (ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (referred to herein as ‘CTPS-IB'): or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS-IB is a potent and selective inhibitor of CTPS1 (see e.g. WO2020245664).
  • CTPS1 inhibitor is a compound of formula (IX):
  • R l is selected from C1-6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R A ;
  • Ring A is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each of R L , R L ‘, and R L " is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two of R L .
  • R L and R L ” groups are taken together with the atoms to whi ch each is attached, to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms i ndependently selected from nitrogen, oxygen, and sulfur; or any one of R L , R L , and R 17 , together with R B forms a 7-10 membered saturated or partially unsaturated fused bicyclic ring;
  • Ring B is selected from phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicydic heterocydic ring having 1-4 heteroatoms independently sdected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur:
  • Ring C is selected from a phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered fused bicyclic heteroaiyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or the bond between Ring B and Ring C is absent, and Ring B and Ring C together form a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic carbocyclic ring; a 7-11 membered fused bicyclic aryl ring; a 7-11 membered saturated or partially unsaturated fused, bridged, or spiro, bicyclic heterocydic ring having 1-4 heteroatoms independently selected from nitrogen
  • R C is independently an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
  • R 1 is C1-6 aliphatic or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; the R group of the sulfonamide moiety is hydrogen or para-methoxybenzyl; and the R L and R L' or R L and R L groups are not taken together with the atoms to which each is attached to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur , or L is
  • Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • Ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and is attached to Ring B in the para position relative to the L group; then Ring A and its R A substituents are other than where * denotes attachment to the moiety and ** denotes attachment to the moiety,
  • CTPS1 inhibitors are disclosed in PCT publication number WO2022087634 which is incorporated by reference in its entirety for the purpose of the CTPS1 inhibitors disclosed therein.
  • a CTPS1 inhibitor may be a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • a CTPS1 inhibitor may be a compound selected from compounds 1-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • a CTPS1 inhibitor may be a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate.
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate (i.e. a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt).
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable salt.
  • the CTPS1 inhibitor is provided in the form of a pharmaceutically acceptable solvate.
  • the CTPS1 inhibitor is provided in free form (i.e. not a salt or solvate).
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.
  • Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418.
  • Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • salts may also be formed with metal ions such as metal salts, such as sodium or potassium salts, and organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • metal ions such as metal salts, such as sodium or potassium salts
  • organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • the CTPS1 inhibitor may form acid or base addition salts with one or more equivalents of the acid or base.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the CTPS1 inhibitor may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • the CTPS1 inhibitor encompasses all isomers of the CTPS1 inhibitors disclosed herein including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the CTPS1 inhibitor encompasses all isotopic forms of the CTPS1 inhibitors provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the CTPS1 inhibitor is provided in a natural isotopic form.
  • the CTPS1 inhibitor is provided in an unnatural variant isotopic form. In one embodiment, the CTPS1 inhibitor is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the CTPS1 inhibitor is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • the CTPS1 inhibitor administered to a subject should be safe and effective, i.e. a CTPS1 inhibitor providing an acceptable balance of desired benefits and undesired side effects.
  • Safe and effective is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer.
  • a desirable effect is typically clinically significant and/or measurable, for instance in the context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms.
  • references herein to administering a safe and effective CTPS1 inhibitor include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and effective CTPS1 inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective dose of CTPS1 inhibitor is thereby achieved by oral administration.
  • the CTPS1 inhibitor is not a CTPS1 inhibitor disclosed in PCT publication number WO2022087634.
  • the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds 1-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z- 1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in claim 1 of WO2022/087634.
  • the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634.
  • a IAP inhibitor for use in the treatment of cancer with a CTPS1 inhibitor.
  • a IAP inhibitor is an agent which directly inhibits IAP activity, such as IAP induced inhibition of apoptosis. Direct inhibition of IAP may be quantified using any suitable assay procedure, though is suitably performed using the IAP protein binding assay or IAP protein degradation assay set out in Example 3.
  • the activity of the IAP inhibitors has been determined using competitive fluorescence polarisation binding affinity assays to calculate inhibitory constant (Ki) values for binding to IAP (Nikolovska-Coleska 2004, Condon 2014) and IAP proteasomal degradation assays to calculate the half maximal effective concentration (ECso) of the IAP inhibitor (Condon 2014).
  • IAP inhibitors of particular interest are those demonstrating Ki values for binding to human IAP of less than 100 nM, such as less than 50 nM, such as less than 10 nM, such as less than 5 nM, such as less than 1 nM.
  • IAP inhibitors of particular interest are those demonstrating Ki values for binding to human IAP of less than 100 nM, such as less than 50 nM, such as less than 10 nM, such as less than 5 nM, such as less than 1 nM using the IAP protein binding assay set out in Example 3.
  • IAP inhibitors of particular interest are those demonstrating ECso values for binding to human IAP of less than 100 nM, such as less than 50 nM, such as less than 30 nM, such as less than 20 nM, such as less than 10 nM, such as less than 5 nM, such as less than 1 nM.
  • IAP inhibitors of particular interest are those demonstrating ECso values for binding to human IAP of less than 100 nM, such as less than 50 nM, such as less than 30 nM, such as less than 20 nM, such as less than 10 nM, such as less than 5 nM, such as less than 1 nM using the IAP protein degradation assay set out in Example 3.
  • IAP inhibitors of particular interest are those demonstrating ECso values for binding to human IAP of less than 100 nM, such as less than 50 nM, such as less than 30 nM, such as less than 20 nM, such as less than 10 nM, such as less than 5 nM, such as less than 1 nM using the clAP1 protein in the IAP protein degradation assay measured at 2 hours as set out in Example 3.
  • IAP inhibitors of particular interest are those demonstrating ECso values for binding to human IAP of less than 300 nM, such as less than 150 nM, such as less than 100 nM, such as less than 70 nM, such as less than 50 nM, such as less than 40 nM, such as less than 20 nM using the clAP2 protein in the IAP protein degradation assay measured at 2 hours as set out in Example 3.
  • the IAP inhibitor is a SMAC mimetic.
  • Particular IAP inhibitors include the following SMAC mimetics:
  • the IAP inhibitor may be birinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor is birinapant.
  • the IAP inhibitor is a pharmaceutically acceptable salt of birinapant.
  • the IAP inhibitor is a pharmaceutically acceptable solvate of birinapant.
  • the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of birinapant.
  • the IAP inhibitor is not birinapant.
  • the IAP inhibitor is not birinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • tolinapant (1-[6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-5-methyl-2-[[(3R)-3-methylmorpholin-4- yl]methyl]piperazin-1-yl]ethenone, CAS: 1799328-86-1) is provided below.
  • the IAP inhibitor may be tolinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor is tolinapant.
  • the IAP inhibitor is a pharmaceutically acceptable salt of tolinapant.
  • the IAP inhibitor is a pharmaceutically acceptable solvate of tolinapant.
  • the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of tolinapant.
  • the IAP inhibitor is not tolinapant.
  • the IAP inhibitor is not tolinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor may be GDC-0152 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor is GDC-0152.
  • the IAP inhibitor is a pharmaceutically acceptable salt of GDC-0152.
  • the IAP inhibitor is a pharmaceutically acceptable solvate of GDC-0152.
  • the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of GDC-0152.
  • the IAP inhibitor is not GDC-0152.
  • the IAP inhibitor is not GDC-0152 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • LCL161 ((2S)-/V-[(1 S)-1-cyclohexyl-2-[(2S)-2-[4-(4-fluorobenzoyl)-1 ,3- thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propenamide, CAS: 1005342-46-0) is provided below.
  • the IAP inhibitor may be LCL161 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor is LCL161.
  • the IAP inhibitor is a pharmaceutically acceptable salt of LCL161.
  • the IAP inhibitor is a pharmaceutically acceptable solvate of LCL161.
  • the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of LCL161.
  • the IAP inhibitor is not LCL161.
  • the IAP inhibitor is not LCL161 or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the structure of xevinapant ((5S,8S,10a/?)-/V-benzhydryl-5-[[(2S)-2- (methylamino)propanoyl]amino]-3-(3-methylbutanoyl)-6-oxo-1 ,2,4,5,8,9,10, 10a- octahydropyrrolo[1 ,2-a][1 ,5]diazocine-8-carboxamide, CAS: 1071992-99-8) is provided below.
  • the IAP inhibitor may be xevinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof. In one embodiment the IAP inhibitor is xevinapant.
  • the IAP inhibitor is a pharmaceutically acceptable salt of xevinapant. In one embodiment the IAP inhibitor is a pharmaceutically acceptable solvate of xevinapant. In one embodiment the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate of xevinapant. In one embodiment, the IAP inhibitor is not xevinapant. In one embodiment, the IAP inhibitor is not xevinapant or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor is selected from the group consisting of birinapant, tolinapant, GDC-0152, LCL161 and xevinapant, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates of any thereof. More suitably the IAP inhibitor is selected from the group consisting of birinapant, tolinapant, GDC-0152, LCL161 and xevinapant, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates of any thereof. More suitably the IAP inhibitor is selected from the list consisting of birinapant, tolinapant and xevinapant, pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates of any thereof. More suitably the IAP inhibitor is birinapant, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • the IAP inhibitor may be provided in the form of a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate.
  • the IAP inhibitor is provided in the form of a pharmaceutically acceptable salt and pharmaceutically acceptable solvate (i.e. a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt).
  • the IAP inhibitor is provided in the form of a pharmaceutically acceptable salt.
  • the IAP inhibitor is provided in the form of a pharmaceutically acceptable solvate.
  • the IAP inhibitor is provide in free form (i.e. not a salt or solvate).
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.
  • Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p.1418.
  • Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • salts may also be formed with metal ions such as metal salts, such as sodium or potassium salts, and organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • metal ions such as metal salts, such as sodium or potassium salts
  • organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • the IAP inhibitor may form acid or base addition salts with one or more equivalents of the acid or base.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the IAP inhibitor may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).
  • the IAP inhibitor encompasses all isomers of the IAP inhibitors disclosed herein including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the IAP inhibitor encompasses all isotopic forms of the IAP inhibitors provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the IAP inhibitor is provided in a natural isotopic form.
  • the IAP inhibitor is provided in an unnatural variant isotopic form.
  • the IAP inhibitor is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, the IAP inhibitor is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • the IAP inhibitors disclosed herein may be made according to the organic synthesis techniques known to those skilled in this field.
  • preparation of birinapant is described in US8283372 and US7517906, which are incorporated herein by reference in their entirety for the purpose of methods of producing the IAP inhibitor birinapant as disclosed herein.
  • the IAP inhibitor administered to a subject should be safe and effective, i.e. a IAP inhibitor providing an acceptable balance of desired benefits and undesired side effects. “Safe and effective” is intended to include a compound that is effective to achieve a desirable effect in treatment of cancer.
  • a desirable effect is typically clinically significant and/or measurable, for instance in the context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms.
  • references herein to administering a safe and effective IAP inhibitor include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and effective IAP inhibitor includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective dose of IAP inhibitor is thereby achieved by oral administration.
  • the invention is typically intended for use with mammalian subjects, in particular human subjects.
  • the combination treatment will typically be administered to a subject in need thereof, in particular a mammalian subject in need thereof, in particular a human subject in need thereof.
  • the invention provides a CTPS1 inhibitor and a IAP inhibitor for use in the treatment of cancer.
  • One aspect of the invention provides the use of a CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a IAP inhibitor.
  • a further aspect of the invention provides the use of a IAP inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.
  • a further aspect of the invention provides the use of a CTPS1 inhibitor and a IAP inhibitor in the manufacture of a medicament for the treatment of cancer.
  • a further aspect of the invention provides a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and a IAP inhibitor.
  • a further aspect of the invention provides a pharmaceutical composition comprising a CTPS1 inhibitor and a IAP inhibitor, suitably for use in the treatment of cancer.
  • the CTPS1 inhibitor and the IAP inhibitor act synergistically in treating the cancer.
  • the CTPS1 inhibitor and the IAP inhibitor act ‘synergistically’ if their combined administration results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone.
  • the CTPS1 inhibitor and the IAP inhibitor act synergistically if they achieve a Bliss score (Bliss 1939; Zheng 2021) of equal to or greater than 10 when applied to a cancer cell line as set out in Example 5.
  • the CTPS1 inhibitor may be administered by any suitable route, which may depend on the nature of the specific agent.
  • exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration.
  • the CTPS1 inhibitor is administered orally.
  • the CTPS1 inhibitor may be provided in the form of a pharmaceutical composition comprising the CTPS1 inhibitor and a pharmaceutically acceptable carrier or excipient.
  • the CTPS1 inhibitor may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution).
  • a solid pharmaceutical composition such as a tablet, capsule or lozenge
  • a liquid pharmaceutical composition such as a suspension, emulsion or solution
  • a liquid formulation will generally consist of a suspension or solution of the CTPS1 inhibitor in a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a tablet formulation can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
  • the pharmaceutical composition is in unit dose form, such as a tablet, capsule or ampoule.
  • the unit dose form is for oral delivery.
  • the pharmaceutical composition may for example contain from 0.1 % to 99.99% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the pharmaceutical composition may contain from 0.01% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the pharmaceutical composition may contain from 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, depending on the method of administration.
  • the pharmaceutical composition may contain from 50 mg to 1000 mg of the carrier, for example from 100 mg to 400 mg, depending on the method of administration.
  • suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer.
  • a plurality of unit does, such as a plurality of tablets, may be taken together.
  • the CTPS1 inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition.
  • the dose provided to a subject will typically be a safe and effective dose, i.e. an amount providing an acceptable balance of desired benefits and undesired side effects.
  • a “safe and effective amount” is intended to include an amount of a compound that is effective to achieve a desirable effect in treatment of a disease-state.
  • a desirable effect is typically clinically significant and/or measurable, for instance in the context of (a) inhibiting the disease-state, i.e. , slowing or arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms.
  • the safe and effective amount is one that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the IAP inhibitor.
  • references herein to administering a safe and effective amount of a compound, such as by a particular administration route include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective amount is thereby achieved by oral administration.
  • the IAP inhibitor may be administered by any suitable route, which may depend on the nature of the specific agent. Exemplary routes include oral, parenteral, buccal, sublingual, nasal or rectal administration. Conveniently, the IAP inhibitor is administered orally.
  • the IAP inhibitor may be provided in the form of a pharmaceutical composition comprising the IAP inhibitor and a pharmaceutically acceptable carrier or excipient.
  • the IAP inhibitor may suitably be delivered in a solid pharmaceutical composition (such as a tablet, capsule or lozenge) or in a liquid pharmaceutical composition (such as a suspension, emulsion or solution).
  • a solid pharmaceutical composition such as a tablet, capsule or lozenge
  • a liquid pharmaceutical composition such as a suspension, emulsion or solution
  • a liquid formulation will generally consist of a suspension or solution of the IAP inhibitor in a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine, or a nonaqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier e.g. an aqueous solvent such as water, ethanol or glycerine, or a nonaqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a tablet formulation can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
  • the pharmaceutical composition is in unit dose form, such as a tablet, capsule or ampoule.
  • the unit dose form is for oral delivery.
  • the pharmaceutical composition may for example contain from 0.1 % to 99.99% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the pharmaceutical composition may contain from 0.01% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the pharmaceutical composition may contain from 0.05 mg to 2000 mg of the active material, for example from 1.0 mg to 500 mg, suitably 5 mg to 15 mg, such as 10 mg, depending on the method of administration.
  • 10 mg may be desirable.
  • the pharmaceutical composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration.
  • suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or longer.
  • a plurality of unit does, such as a plurality of tablets, may be taken together.
  • the IAP inhibitor is administered daily for a period 5 weeks.
  • the IAP inhibitor may be administered at a daily dose of 20 mg for week 1 , 50 mg for week 2, 100 mg for week 3, 200 mg for week 4 and 400 mg for week 5.
  • the IAP inhibitor may be administered at a daily dose of up to 600 mg, suitably 1.0 mg to 500 mg.
  • the IAP inhibitor is administered orally, such as administered orally in a solid pharmaceutical composition.
  • the dose provided to a subject will typically be a safe and effective dose, i.e. an amount providing an acceptable balance of desired benefits and undesired side effects.
  • a “safe and effective amount” is intended to include an amount of a compound that is effective to achieve a desirable effect in treatment of a disease-state.
  • a desirable effect is typically clinically significant and/or measurable, for instance in the context of (a) inhibiting the disease-state, i.e., slowing or arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state or a reduction in associated symptoms.
  • the safe and effective amount is one that is sufficient to achieve the desirable effect when the CTPS1 inhibitor is administered with the IAP inhibitor.
  • references herein to administering a safe and effective amount of a compound, such as by a particular administration route include achieving the safe and effective amount via a single dose or by plural doses, such as administered by the specified administration route.
  • orally administering a safe and effective amount includes both orally administering a single dose and orally administering any plural number of doses, provided that a safe and effective amount is thereby achieved by oral administration.
  • the CTPS1 inhibitor and IAP inhibitor may be administered separately, sequentially or simultaneously.
  • the CTPS1 inhibitor may be administered before the IAP inhibitor.
  • the IAP inhibitor may be administered before the CTPS1 inhibitor.
  • the CTPS1 inhibitor and/or IAP inhibitor may be administered intermittently. Intermittently in this context means that the CTPS1 inhibitor and/or the IAP inhibitor are not administered every day of a treatment cycle (e.g. the CTPS1 inhibitor and/or the IAP inhibitor are administered for 4 days in each 7 day period of a treatment cycle). It will be understood that when the CTPS1 inhibitor and IAP inhibitor are both administered intermittently, they need not be administered according to the same schedule.
  • the CTPS1 inhibitor and/or IAP inhibitor may be administered continuously i.e. administered at least daily in a treatment cycle (e.g. the CTPS1 inhibitor and/or the IAP inhibitor are administered each day of a treatment cycle).
  • the CTPS1 inhibitor is administered intermittently and the IAP inhibitor is administered intermittently.
  • the CTPS1 inhibitor is administered continuously and the IAP inhibitor is administered continuously.
  • the CTPS1 inhibitor is administered intermittently and the IAP inhibitor is administered continuously.
  • the CTPS1 inhibitor is administered continuously and the IAP inhibitor is administered intermittently.
  • the CTPS1 inhibitor and the IAP inhibitor may be delivered in co-formulation (where compatible with co-formulation and whether the dosage regimes of the two agents allow) or in separate formulations. Most suitably the CTPS1 inhibitor and the IAP inhibitor are delivered in co-formulation or in separate formulations which are simultaneously administered. Alternatively, if delivered in separate formulations, the CTPS1 inhibitor and the IAP inhibitor may be delivered at different times.
  • CTPS1 inhibitor or a pharmaceutical composition comprising such, such as a tablet or capsule
  • IAP inhibitor or a pharmaceutical composition comprising such, such as a tablet or capsule
  • the CTPS1 inhibitor and IAP inhibitor may be provided in the form of a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising a IAP inhibitor.
  • the CTPS1 inhibitor and IAP inhibitor may be provided in the form of a kit of parts comprising a first container comprising a CTPS1 inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule) and a second container comprising a IAP inhibitor (or a pharmaceutical composition comprising such, such as a tablet or capsule).
  • Treatment with the CTPS1 inhibitor and IAP inhibitor may be combined with one or more further pharmaceutically acceptable active ingredients, which may be selected from: anti-mitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents for example adriamycin and bleomycin; topoisomerase inhibitors for example etoposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; PI3 kinase inhibitors for example idelalisib; mTor inhibitors for example everolimus and temsirolimus; proteasome inhibitors for example bortezomib; histone deacetylase inhibitors for example panobino
  • T reatment with the CTPS1 inhibitor and IAP inhibitor may be combined with one or more agents selected from the list consisting of BCL2 inhibitors, ATR inhibitors, CHEK1 inhibitors and WEE1 inhibitors.
  • BCL2 inhibitors include those disclosed in PCT/EP2023/055217, which is incorporated by reference in its entirety for the purpose of the BCL2 inhibitors disclosed therein.
  • ATR inhibitors include those disclosed in PCT/EP2023/055219, which is incorporated by reference in its entirety for the purpose of the ATR inhibitors disclosed therein.
  • Suitable CHEK1 inhibitors include those disclosed in PCT/EP2023/055220, which is incorporated by reference in its entirety for the purpose of the CHEK1 inhibitors disclosed therein.
  • Suitable WEE1 inhibitors include those disclosed in PCT/EP2023/055222, which is incorporated by reference in its entirety for the purpose of the WEE1 inhibitors disclosed therein.
  • CTPS1 inhibitor, IAP inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing. If administered simultaneously, the CTPS1 inhibitor and IAP inhibitor may be e.g. (a) formulated together but separately from the further pharmaceutically acceptable active ingredient, (b) formulated separately from each other and separately from the further pharmaceutically acceptable active ingredient (c) formulated together with the further pharmaceutically acceptable active ingredient.
  • the CTPS1 inhibitor, the IAP inhibitor and the additional pharmaceutically acceptable active ingredients may each be administered in any combination of separate, sequential or simultaneous dosing.
  • the CTPS1 inhibitor, IAP inhibitor and the additional pharmaceutically acceptable active ingredients may be e.g. (a) formulated together but separately from the further pharmaceutically acceptable active ingredient, (b) formulated separately from each other and separately from the further pharmaceutically acceptable active ingredient, (c) formulated together with the further pharmaceutically acceptable active ingredient; (d) formulated separately from each other, but one of the CTPS1 inhibitor or IAP inhibitor formulated together with the further pharmaceutically acceptable active ingredient.
  • the further pharmaceutically acceptable active ingredient may be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • the further pharmaceutically acceptable active ingredient may be selected from azacitidine, decitabine, or cytarabine.
  • anticancer antibodies such as those selected from the group consisting of anti-CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin.
  • anti-CD20 antibodies such as obinutuzumab, ofatumumab, tositumomab or rituximab
  • other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtans
  • CTPS1 inhibitor and IAP inhibitor may also be administered in combination with radiotherapy, surgery, hyperthermia therapy or cryotherapy.
  • the cancer is a cancer which is susceptible to replication stress or has high pre-existing levels of replication stress.
  • a ‘high’ level it is meant that the cancer has a pre-existing level of replication stress which is higher than an average cancer.
  • the cancer is a haematological cancer, such as acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T- cell non-Hodgkin lymphoma (including natural killer/T-cell lymphoma, adult T-cell leukaemia/lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple mye
  • T cell lymphoma diffuse large B cell lymphoma, plasma cell myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia or peripheral T cell lymphoma.
  • a further haematological cancer of interest is T-cell prolymphocytic leukemia.
  • Other haematological cancers of interest are myelodysplastic syndromes (MDS), such as MDS with single lineage dysplasia, MDS with multilineage dysplasia or MDS with excess blasts.
  • MDS myelodysplastic syndromes
  • the cancer is a non-haematological cancer, such as selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • a non-haematological cancer such as selected from the group consisting of colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma, melanoma, bone cancer, head and neck cancer, breast cancer, brain cancers, prostate cancer, renal cancer, thyroid cancer and neuroblastoma.
  • the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer, oesophageal cancer, sarcoma, bladder cancer, pancreatic cancer, ovarian cancer, lung cancer, mesothelioma and melanoma. More suitably the non-haematological cancer is selected from colorectal cancer, bile duct cancer, endometrial cancer, hepatic cancer, gastric cancer and oesophageal cancer.
  • the non- haematological cancer may be selected from prostate cancer, pancreatic cancer, ovarian cancer, lung cancer, renal cancer, colorectal cancer or breast cancer.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, lung cancer, colorectal cancer, pancreatic cancer and prostate cancer. More suitably the cancer is selected from the group consisting of breast cancer, ovarian cancer, lung cancer and colorectal cancer.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit of the invention is not for use in the treatment of CTPS2 deficient cancer in a subject.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit of the invention may be for administration to a subject identified as having a cancer expected to be susceptible to treatment by a CTPS1 inhibitor and a IAP inhibitor.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit of the invention may be for administration to a subject from whom a sample of cancer cells has been shown to be susceptible to treatment by a CTPS1 inhibitor and a IAP inhibitor.
  • a ‘susceptible’ cancer or cancer cell sample in this context is one which is associated with generally demonstrating a benefit from the treatment according to the invention relative to treatment with CTPS1 or IAP inhibitors alone, e.g. additive or suitably synergistic effects - high in vivo efficacy, reduction in the dose required for effect in vivo and/or an improved safety profile/reduced side effects.
  • the invention is further exemplified by the following non-limiting examples.
  • CTPS1-IA is 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)tetrahydro-2H-pyran-4-carboxamide.
  • CTPS-I B is /V-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4- yl)tetrahydro-2/7-pyran-4-carboxamide.
  • 3x human CTPS1 protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume per well of 3x human CTPS1 protein was mixed with 2uL per well of 3x test compound (compound prepared in 1x assay buffer to an appropriate final 3x compound concentration respective to the concentration response curve designed for the compounds under test) for 10 minutes at 25°C.
  • the enzymatic reaction was then initiated by addition of a 2uL per well volume of a pre-mixed substrate mix (UltraPure ATP from ADP-GloTM Max kit (0.31 mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (0.186mM)) and the mixture was incubated for an appropriate amount of time within the determined linear phase of the reaction at 25°C under sealed plate conditions with constant agitation at 500 revolutions per minute (rpm).
  • a pre-mixed substrate mix UltraPure ATP from ADP-GloTM Max kit (0.31 mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (0.186mM
  • ADP-GloTM Max reagent was added for 60 minutes (6pL per well) and subsequently ADP-GloTM Max development reagent was added for 60 minutes (12uL per well) prior to signal detection in a microplate reader (EnVision® Multilabel Reader, Perkin Elmer). Following each reagent addition over the course of the assay, assay plates were pulse centrifuged for 30 seconds at 500rpm.
  • the enzyme converts ATP to ADP and the ADP-GloTM Max reagent subsequently depletes any remaining endogenous ATP in the reaction system.
  • the ADP-GloTM Max detection reagent converts the ADP that has been enzymatically produced back into ATP and using ATP as a substrate together with luciferin for the enzyme luciferase, light is generated which produces a detectable luminescence.
  • the luminescent signal measured is directly proportional to the amount of ADP produced by the enzyme reaction and a reduction in this signal upon compound treatment demonstrates enzyme inhibition. The percentage inhibition produced by each concentration of compound was calculated using the equation shown below: 100
  • RF/MS assays for both human CTPS1 and CTPS2 were performed in assay buffer consisting of 50mM HEPES (Merck), 20mM MgCI 2 , 5mM KCI, 1 mM DTT, 0.01% Tween-20, pH to 8.0 accordingly.
  • Human full-length active C-terminal FLAG-His- tag CTPS1 (UniProtKB - P17812, CTPS[1-591]-GGDYKDDDDKGGHHHHHHHH, SEQ ID NO: 1) was obtained from Proteros biostructures GmbH.
  • Human CTPS (1 or 2) protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction.
  • a 2uL volume per well of 2x CTPS (1 or 2) protein was mixed with 40nL of compound using acoustic (ECHO) delivery and incubated for 10 minutes at 25°C.
  • ECHO acoustic
  • Each isoform enzymatic reaction was subsequently initiated by addition of 2uL per well of a 2x substrate mix in assay buffer.
  • hCTPSI ATP (0.3mM), UTP (0.2mM), GTP (0.07mM) and L-glutamine (0.1 mM).
  • hCTPS2 ATP (0.1 mM), UTP (0.04mM), GTP (0.03mM) and L- glutamine (0.1 mM).
  • the enzyme converts UTP to CTP.
  • Highly specific and sensitive multiple reaction monitoring (MRM) MS methods may be optimised for the detection of the enzymatic reaction product, CTP, and the stable isotope labelled product standard 13 C 9 - 15 N 3 -CTP. Readout for data analysis was calculated as the ratio between the peak area of the product CTP and the internal standard 13 C 9 - 15 N 3 -CTP. For data reporting, the following equation was used:
  • Example 3 Human IAP Inhibition IAP protein binding assay The ability of IAP inhibitors to bind IAP proteins is established in a fluorescence polarisation assay which measures the displacement of a fluorescent peptide containing an IAP binding motif, for example ⁇ -aminobutyric acid-RPFK(5-carboxyfluorescein)-NH2 (SEQ ID NO: 3), from the baculovirus IAP repeat domain of an IAP family protein such as XIAP, cIAP1, cIAP2 or ML-IAP.
  • an IAP binding motif for example ⁇ -aminobutyric acid-RPFK(5-carboxyfluorescein)-NH2 (SEQ ID NO: 3
  • an IAP family protein such as XIAP, cIAP1, cIAP2 or ML-IAP.
  • IAP binding motifs can be incubated with increasing concentrations of an IAP family protein, and polarization values measured at an excitation wavelength at 485 nm and an emission wavelength at 530 nm.
  • IAP proteins can be generated by expression as glutathione S-transferase (GST) fusions in E. coli cells. Protein expression can be induced by addition of IPTG and cultures incubated at 18°C overnight. Recovered cells can be sonicated in lysis buffer and GST-bound protein recovered using binding to glutathione Sepharose and purified using a Sephadex 75 column, a Superdex S200 column or other equivalent (Nikolovska-Coleska 2004, Condon 2014).
  • IAP protein degradation assay The ability of IAP inhibitors to bind IAP proteins is established in a cellular protein degradation assay.
  • IAP proteins tagged with green fluorescent protein (GFP) can be expressed in human cells, for example the malignant melanoma cell line A375, by transient or stable transfection of a plasmid or viral vector expression construct.
  • Human cells expressing a GFP- tagged IAP protein can then be exposed to various concentrations of an IAP antagonist for a short period of time, for example 2 hours, followed by measurement of GFP intensity by flow cytometry using 488 nm excitation and 530 nm emission.
  • the binding of IAP inhibitors to human IAP proteins activates autoubiquitylation and subsequent proteasomal degradation of the protein.
  • Exposure of human cells expressing a GFP-tagged IAP protein to an IAP inhibitor can, therefore, be used to measure the cellular potency of the IAP inhibitor by measurement of GFP intensity.
  • the difference in GFP intensity between baseline and following drug exposure is used to calculate the half maximal effective concentration (EC50) of the IAP inhibitor (Condon 2014).
  • CTPS1 Involvement in the Proliferation of Cancer Cells Pathways involved in providing the key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed to be up-regulated in tumors and neoplastic cells.
  • CTPS activity is upregulated in a range of tumour types of both haematological and non-haematological origin, although heterogeneity is observed among patients.
  • CTPS1 was found by the present inventors to be essential for the proliferation of human cancer cells derived from a broad range of haematological and solid tumour types, whereas CTPS2 was invariably redundant.
  • This analysis used data from the Achilles project where every gene in the human genome was independently deleted using CRIPR technology in each of 324 human cancer cell lines, and the effects of each gene deletion was assessed using an in vitro proliferation assay (Behan 2019).
  • This dataset has subsequently been expanded to include data from 1,032 human cancer cell lines (Cancer Dependency Map: https://depmap.org/). The effects of deletion of different genes in the pyrimidine synthesis pathway were assessed (see Fig.2).
  • CTPS2 had no effect on cancer cell proliferation.
  • deletion of genes in the salvage pathway (UCK1, UCK2) had minimal effect on cell proliferation.
  • CMPK1 had a marked effects on cell proliferation, consistent with CMPK1 being an essential gene.
  • Deletion of CTPS1, UMPS, DHODH or CAD inhibited cancer cell proliferation with an effect that is consistent with dependency of cancer cells on the products of these genes; inhibition of CTPS1 produced the greatest impairment of cancer cell proliferation.
  • Example 5 Effect of Combined Treatment with a CTPS1 inhibitor and an IAP Inhibitor
  • In vitro proliferation assays were performed using human cancer cell lines to assess synergy between the antiproliferative effects of a CTPS1 inhibitor and an IAP inhibitor. Cell lines were plated in triplicate at a density of 4x10 3 cells/well (in 96 well plates) in 80 ⁇ L medium.
  • CTPS1 inhibitor CPS1-IA
  • IAP inhibitor birinapant
  • 6x6 matrices above, at and below the single agent IC50 value for the cell line being studied, as well as a no drug condition
  • cell viability was assessed after 72 hours incubation using a metabolic reagent such as CellTiter-Glo (Promega).
  • Combined effects were assessed by calculating Bliss scores (Bliss 1939; Zheng 2021); A value of -10 to ⁇ 10 indicates an additive effect and a value of ⁇ 10 indicates synergy.
  • Fig.3 shows representative data from 8 human cancer cell lines, representing colorectal, ovarian, pancreatic, prostate, breast and lung cancers, exposed to the CTPS1 inhibitor CTPS1- IA combined with the IAP inhibitor birinapant. Synergy was observed in 4 of the 8 cell lines (CAL- 120 (breast), A2780 (ovarian), HCT116 (lung) and COLO205 (colorectal) Bliss scores 14 - 24), with additive effects observed in the other 4 cell lines. For comparison, a DNK-PK inhibitor (AZD7648) combined with CTPS1A was tested in the same 8 cell lines and Bliss scores from -1.9 to 3.1 were observed.
  • an IAP inhibitor combined with a CTPS1 inhibitor may provide a greater effect than other agents relating to the DDR pathway combined with a CTPS1 inhibitor.
  • CTPS1 inhibitor in the manufacture of a medicament for the treatment of cancer with a IAP inhibitor.
  • IAP inhibitor in the manufacture of a medicament for the treatment of cancer with a CTPS1 inhibitor.
  • CTPS1 inhibitor and a IAP inhibitor in the manufacture of a medicament for the treatment of cancer.
  • a method of treating cancer in a subject which method comprises administering to the subject a CTPS1 inhibitor and a IAP inhibitor.
  • a pharmaceutical composition comprising a CTPS1 inhibitor and a IAP inhibitor.
  • a kit of parts comprising: a) a first container comprising a CTPS1 inhibitor; and b) a second container comprising a IAP inhibitor.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 9, wherein the CTPS1 inhibitor has an IC 50 of 10 uM or lower in respect of human CTPS1 enzyme.
  • Clause 11 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 10, wherein the CTPS1 inhibitor has an IC 50 of 1 uM or lower in respect of human CTPS1 enzyme.
  • Clause 12 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 11, wherein the CTPS1 inhibitor has an IC 50 of 100nM or lower in respect of human CTPS1 enzyme.
  • Clause 14 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 13, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 2-fold.
  • Clause 15 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 14, wherein the CTPS1 inhibitor has a selectivity for human CTPS1 over human CTPS2 of at least 30-fold.
  • CTPS1 inhibitor IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 17, wherein the CTPS1 inhibitor is a compound of formula (I) wherein R1 is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3 is H, CH3, halo, OC1-2alkyl or CF3; R4 and R5 are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3- 6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3- 6cycloalkyl or C3-6heterocycloalkyl ring; R6 is H or C1-3alkyl; Ar1 is a 6-
  • CTPS1 inhibitor is a compound of formula (II): wherein R 1 is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3 is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3 together with R 5 forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4 and R 5 are each independently H, halo, C 1-6 alkyl
  • CTPS1 inhibitor is a compound of formula (IV): wherein: (a) when R4, R5, X, Y and R1 are as follows: then W is N, CH or CF; (b) when R4, R5, X, W and R1 are as follows: then Y is CH or N; (c) when W, X, Y and R 1 are as follows: then R4 and R5 are joined to form the following structures: (d) when W, R 4 , R 5 , X and Y are as follows: then R 1 is methyl or cyclopropyl; and (e) the compound is selected from the group consisting of: or a pharmaceutically acceptable salt and/or
  • CTPS1 inhibitor is a compound of formula (V): (a) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: , then R 4 and R 5 together with the carbon atom to which they attached form: or (b) when A, V, W, X, Y, Z, R 1 , R 10 and R 12 are as follows: , then R4 and R5 together with the carbon atom to which they are attached form: or (c) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows: : then R1 is or (d) when A, V, W, X, Y, Z, R4, R5, R10 and R12 are as follows: : then R1 is or (d) when
  • CTPS1 inhibitor is a compound of formula (VI): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and wherein R3b3c is R3b or R3c as defined below; wherein when B is (B-a) the compound of formula (VI) is a compound of formula (VI-a): wherein: A a is A aa or A ba ; wherein: A aa is an amine linker having the following structure: -NH-, -CH 2 NH- or -NHCH 2 -; A ba is an amide linker having the following structure: -C
  • Clause 36 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 35, wherein the CTPS1 inhibitor is in its free form.
  • CTPS1 inhibitor IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 17, wherein the CTPS1 inhibitor is 4-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro- 2H-pyran-4-carboxamide , or a pharmaceutically acceptable salt thereof.
  • CTPS1 inhibitor is N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide (‘CTPS1-IB’): , or a pharmaceutically acceptable salt thereof.
  • CTPS1-IB N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide
  • CTPS1-IB N-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide
  • CTPS1-IB N-
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 43 to 47, wherein the Ki value of the IAP inhibitor for binding to human IAP is established using the IAP protein binding assay set out in Example 3.
  • Clause 50. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 49, wherein the EC50 value of the IAP inhibitor for binding to human IAP is less than 50 nM.
  • Clause 51. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 50, wherein the EC50 value of the IAP inhibitor for binding to human IAP is less than 30 nM.
  • Clause 56. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 49 to 55, wherein the EC 50 value of the IAP inhibitor for binding to human IAP is established using the IAP protein degradation assay set out in Example 3.
  • Clause 57. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 49 to 56, wherein cIAP1 protein is used in the IAP protein degradation assay.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 60, wherein the IAP inhibitor is selected from birinapant, tolinapant, GDC-0152, LCL161 and xevinapant, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • the IAP inhibitor is selected from birinapant, tolinapant, GDC-0152, LCL161 and xevinapant, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • Clause 62 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 61, wherein the IAP inhibitor is selected from birinapant, tolinapant and xevinapant, pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • the IAP inhibitor is GDC-0152 : ((2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2- (methylamino)propanoyl]amino]acetyl]-N-(4-phenylthiadiazol-5-yl)pyrrolidine-2-carboxamide), pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable solvates thereof.
  • the IAP inhibitor is xevinapant:
  • Clause 70. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 67, wherein the IAP inhibitor is a pharmaceutically acceptable solvate.
  • Clause 71. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 67, wherein the IAP inhibitor is a pharmaceutically acceptable salt and a pharmaceutically acceptable solvate.
  • Clause 72. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 63, wherein the IAP inhibitor is birinapant: .
  • Clause 73 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 72, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof and the IAP inhibitor is birinapant.
  • Clause 74 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 73, wherein the CTPS1 inhibitor is CTPS-IA or a pharmaceutically acceptable salt thereof and the IAP inhibitor is birinapant.
  • Clause 75 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 74, wherein the IAP inhibitor is provided in a natural isotopic form.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 75 wherein the CTPS1 inhibitor and the IAP inhibitor act synergistically in treating the cancer.
  • Clause 77. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 76 wherein the combined administration of the CTPS1 inhibitor and the IAP inhibitor results in a beneficial effect greater than the sum of the beneficial effects of each agent administered alone.
  • Clause 79. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 78, wherein the IAP inhibitor and the CTPS1 inhibitor are administered to a mammal.
  • Clause 80. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 79, wherein the IAP inhibitor and the CTPS1 inhibitor are administered to a human.
  • Clause 82. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 81, wherein the CTPS1 inhibitor and the IAP inhibitor are administered separately.
  • Clause 83. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 81, wherein the CTPS1 inhibitor and the IAP inhibitor are administered simultaneously.
  • Clause 84 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 80, wherein the CTPS1 inhibitor and the IAP inhibitor are co- formulated.
  • Clause 85 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 84, wherein the CTPS1 inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration.
  • Clause 86 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 85, wherein the CTPS1 inhibitor is administered orally.
  • Clause 87 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 86, wherein the IAP inhibitor is administered by oral, parenteral, buccal, sublingual, nasal or rectal administration.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 89 wherein the one or more further pharmaceutically acceptable active ingredients are selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 89 wherein the one or more further pharmaceutically acceptable active ingredients are selected from zacitidine, decitabine, or cytarabine.
  • anticancer antibodies such as those selected from the group consisting of anti- CD20 antibodies (such as obinutuzumab, ofatumumab, tositumomab or rituximab) or other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, brentuximab, panitumumab, catumaxomab, bevacizumab, cetuximab, traztuzumab and gentuzumab ozogamycin.
  • anti- CD20 antibodies such as obinutuzumab, ofatumumab, tositumomab or rituximab
  • other antibodies such as olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtans
  • Clause 93 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 92, administered in combination with radiotherapy.
  • Clause 94 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 93, administered in combination with surgery.
  • Clause 95 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 94, administered in combination with hyperthermia therapy.
  • Clause 96 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 95, administered in combination with cryotherapy.
  • Clause 98. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 97, wherein the cancer is a non-haematological cancer.
  • Clause 99. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 98, wherein the cancer is selected from the group consisting of bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma. Clause 100.
  • Clause 101. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 97, wherein the cancer is a haematological cancer.
  • CTPS1 inhibitor The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 102, wherein the haematological cancer is selected from the list consisting of B-cell non-Hodgkin lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), multiple myeloma and plasma cell leukaemia.
  • B-cell non-Hodgkin lymphoma including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma
  • multiple myeloma multiple myeloma and plasma cell leukaemia.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 103 wherein the haematological cancer is selected from the list consisting of T cell lymphoma, diffuse large B cell lymphoma, plasma cell myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia or peripheral T cell lymphoma.
  • Clause 105 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 104, wherein the haematological cancer is T cell lymphoma.
  • Clause 106. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 104, wherein the haematological cancer is diffuse large B cell lymphoma.
  • Clause 110. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 104, wherein the haematological cancer is peripheral T cell lymphoma.
  • Clause 112. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 97, wherein the cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumours, colorectal cancer, esophagogastric cancer, breast cancer, endometrial cancer renal cancer, sarcoma, hepatic cancer, pancreatic cancer, bladder cancer, thyroid cancer, ovarian cancer, head and neck cancer, mesothelioma and biliary tract cancer.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 112 wherein the cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumours, colorectal cancer, esophagogastric cancer, breast cancer, endometrial cancer renal cancer, sarcoma, hepatic cancer and pancreatic cancer.
  • Clause 114 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 113, wherein the cancer is selected from the list consisting of leukemia, lymphoma, lung cancer, bone cancer, melanoma, prostate cancer, brain tumours and colorectal cancer.
  • the CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 113 wherein the cancer is selected from the list consisting of colorectal, ovarian, pancreatic, prostate, breast and lung cancers.
  • Clause 116. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 113, wherein the cancer is selected from the list consisting of breast, ovarian, lung and colorectal cancer.
  • Clause 118. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 116, wherein the cancer is ovarian cancer.
  • Clause 123. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 122, wherein the CTPS1 inhibitor and IAP inhibitor are administered orally.
  • Clause 124. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 123, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition. Clause 124.
  • Clause 125. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 123, wherein the CTPS1 inhibitor is in a solid pharmaceutical composition and the IAP inhibitor is in a solid pharmaceutical composition.
  • Clause 126. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 125, wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition.
  • Clause 128. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 125, wherein the CTPS1 inhibitor is administered orally in a solid pharmaceutical composition and the IAP inhibitor is administered orally in a solid pharmaceutical composition.
  • Clause 129. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 128, wherein the IAP inhibitor is administered at a daily dose of up to 600 mg, suitably a daily dose of 1.0 mg to 500 mg. Clause 130.
  • CTPS1 inhibitor use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is: N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H- pyran-4-carboxamide , or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the IAP inhibitor is birinapant, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause 131.
  • CTPS1 inhibitor use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-carboxamide: , or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof; and the IAP inhibitor is birinapant, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof. Clause 132.
  • Clause 133. The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is not a CTPS1 inhibitor as defined in WO2022/087634.
  • Clause 134 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is a CTPS1 inhibitor disclosed in PCT publication number WO2022087634. Clause 135.
  • CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to clause 134 wherein the CTPS1 inhibitor is a CTPS1 inhibitor disclosed in claim 1 of PCT publication number WO2022087634.
  • Clause 136 The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • CTPS1 inhibitor IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 129, wherein the CTPS1 inhibitor is not (i) a compound described in any one of claims 1 to 31 of WO2022087634 or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, (ii) a compound selected from compounds I-1 to I-286 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof, or (iii) a compound selected from compounds Z-1 to Z-10 of WO2022087634, or a pharmaceutically acceptable salt and/or pharmaceutically acceptable solvate thereof.
  • Clause 139 Clause 139.
  • CTPS1 inhibitor The CTPS1 inhibitor, IAP inhibitor, use, method, composition or kit according to any one of clauses 1 to 129, wherein the cancer is not CTPS2 deficient cancer.
  • Cancer Dependency Map https://depmap.org/ Cetraro et al. Cancers (Basel).2022 Mar 25;14(7):1671. Condon et al.

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne entre autres des méthodes de traitement du cancer comprenant l'administration à un sujet d'un inhibiteur de la cytidine triphosphate synthase 1 (CTPS1) et d'un inhibiteur de l'inhibiteur de l'apoptose (IAP).
PCT/EP2023/087318 2022-12-21 2023-12-21 Combinaisons d'un inhibiteur de ctps1 et d'un inhibiteur d'iap pour une utilisation dans le traitement du cancer WO2024133721A1 (fr)

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517906B2 (en) 2005-02-25 2009-04-14 Tetralogic Pharmaceuticals Corporation Dimeric IAP inhibitors
US8283372B2 (en) 2009-07-02 2012-10-09 Tetralogic Pharmaceuticals Corp. 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic
WO2019106146A1 (fr) 2017-11-30 2019-06-06 Step Pharma S.A.S. Composés
WO2019106156A1 (fr) 2017-11-30 2019-06-06 Step Pharma S.A.S. Composés
WO2019180244A1 (fr) 2018-03-23 2019-09-26 Step Pharma S.A.S. Dérivés d'aminopyrimidine utilisés comme inhibiteurs de ctps1
WO2019179652A1 (fr) 2018-03-23 2019-09-26 Step Pharma S.A.S. Dérivés d'aminopyrimidine utilisés comme inhibiteurs de ctps1
WO2020083975A1 (fr) 2018-10-23 2020-04-30 Step Pharma S.A.S. Dérivés d'aminopyrimidine/pyrazine en tant qu'inhibiteurs de ctps1
WO2020245665A1 (fr) 2019-06-04 2020-12-10 Step Pharma S.A.S. Dérivés de n-(4-(5-chloropyridin-3-yl)phényl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) butanamide et des composés apparentés servant d'inhibiteurs de ctps1 humains pour le traitement de maladies prolifératives
WO2020245664A1 (fr) 2019-06-04 2020-12-10 Step Pharma S.A.S. Dérivés de n-(5-(6-éthoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(méthylsulfonamido)pyrimidin-4-yl) tétrahydro-2h-pyran-4-carboxamide et des composés apparentés servant d'inhibiteurs de ctps1 humains pour le traitement de maladies prolifératives
WO2021053403A1 (fr) 2019-09-20 2021-03-25 Step Pharma S.A.S. Inhibiteurs de sulfonamide utilisés en tant u'inhibiteurs de ctps1
WO2021053402A2 (fr) 2019-09-20 2021-03-25 Step Pharma S.A.S. Composés
WO2022087634A1 (fr) 2020-10-23 2022-04-28 Nimbus Clotho, Inc. Inhibiteurs de ctps1 et leurs utilisations

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517906B2 (en) 2005-02-25 2009-04-14 Tetralogic Pharmaceuticals Corporation Dimeric IAP inhibitors
US8283372B2 (en) 2009-07-02 2012-10-09 Tetralogic Pharmaceuticals Corp. 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic
WO2019106146A1 (fr) 2017-11-30 2019-06-06 Step Pharma S.A.S. Composés
WO2019106156A1 (fr) 2017-11-30 2019-06-06 Step Pharma S.A.S. Composés
WO2019180244A1 (fr) 2018-03-23 2019-09-26 Step Pharma S.A.S. Dérivés d'aminopyrimidine utilisés comme inhibiteurs de ctps1
WO2019179652A1 (fr) 2018-03-23 2019-09-26 Step Pharma S.A.S. Dérivés d'aminopyrimidine utilisés comme inhibiteurs de ctps1
WO2020083975A1 (fr) 2018-10-23 2020-04-30 Step Pharma S.A.S. Dérivés d'aminopyrimidine/pyrazine en tant qu'inhibiteurs de ctps1
WO2020245665A1 (fr) 2019-06-04 2020-12-10 Step Pharma S.A.S. Dérivés de n-(4-(5-chloropyridin-3-yl)phényl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) butanamide et des composés apparentés servant d'inhibiteurs de ctps1 humains pour le traitement de maladies prolifératives
WO2020245664A1 (fr) 2019-06-04 2020-12-10 Step Pharma S.A.S. Dérivés de n-(5-(6-éthoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(méthylsulfonamido)pyrimidin-4-yl) tétrahydro-2h-pyran-4-carboxamide et des composés apparentés servant d'inhibiteurs de ctps1 humains pour le traitement de maladies prolifératives
WO2021053403A1 (fr) 2019-09-20 2021-03-25 Step Pharma S.A.S. Inhibiteurs de sulfonamide utilisés en tant u'inhibiteurs de ctps1
WO2021053402A2 (fr) 2019-09-20 2021-03-25 Step Pharma S.A.S. Composés
WO2022087634A1 (fr) 2020-10-23 2022-04-28 Nimbus Clotho, Inc. Inhibiteurs de ctps1 et leurs utilisations

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
BEHAN ET AL., NATURE, vol. 568, no. 7753, April 2019 (2019-04-01), pages 511 - 516
BLISS, ANN. APPL. BIOL., vol. 26, 1939, pages 585 - 615
CETRARO ET AL., CANCERS (BASEL, vol. 14, no. 7, 25 March 2022 (2022-03-25), pages 1671
CONDON ET AL., J MED CHEM., vol. 57, no. 9, 8 May 2014 (2014-05-08), pages 3666 - 77
CONG HUI ET AL: "Inhibitor of Apoptosis Protein (IAP) Antagonists in Anticancer Agent Discovery: Current Status and Perspectives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 12, 27 June 2019 (2019-06-27), US, pages 5750 - 5772, XP055821884, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b01668> DOI: 10.1021/acs.jmedchem.8b01668 *
MARTIN ET AL., JCI INSIGHT, vol. 5, no. 5, 12 March 2020 (2020-03-12), pages e133880
MARTIN ET AL., NATURE, vol. 510, no. 7504, 12 June 2014 (2014-06-12), pages 288 - 292
MINET ET AL., LIFE SCIENCE ALLIANCE, vol. 6, no. 9, 22 June 2023 (2023-06-22), pages e202302066
NIKOLOVSKA-COLESKA ET AL., ANAL BIOCHEM., vol. 332, no. 2, 15 September 2004 (2004-09-15), pages 261 - 73
PRAJWAL BODDU ET AL: "SMAC mimetics as potential cancer therapeutics in myeloid malignancies", BRITISH JOURNAL OF HAEMATOLOGY, JOHN WILEY, HOBOKEN, USA, vol. 185, no. 2, 5 March 2019 (2019-03-05), pages 219 - 231, XP071104825, ISSN: 0007-1048, DOI: 10.1111/BJH.15829 *
S. FULDA: "Promises and Challenges of Smac Mimetics as Cancer Therapeutics", CLINICAL CANCER RESEARCH, vol. 21, no. 22, 15 November 2015 (2015-11-15), US, pages 5030 - 5036, XP055397813, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-15-0365 *
SUN ZHE ET AL: "Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells", CANCER RESEARCH, vol. 82, no. 6, 15 March 2022 (2022-03-15), US, pages 1013 - 1024, XP093042823, ISSN: 0008-5472, Retrieved from the Internet <URL:https://watermark.silverchair.com/1013.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAsgwggLEBgkqhkiG9w0BBwagggK1MIICsQIBADCCAqoGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMsnAq-TV4P_8eLB_bAgEQgIICewUVYb4Do4Dlm7YcN2CXdWKyzZuEiDRGynAMND55aRlp8mkXchjxyd-TC2tnpgU5zKE4b48465urv92jkgM5fvitSYMafLA> DOI: 10.1158/0008-5472.CAN-21-1707 *
VAN KUILENBURG ET AL., BIOCHIM BIOPHYS ACTA, vol. 1492, no. 2-3, 24 July 2000 (2000-07-24), pages 548 - 552
ZHENG ET AL., BIORXIV, 2021.06.01.446564

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