Treatment of oncogene-driven cancers

Abstract

The present disclosure provides methods of treating a subject identified as having an oncogene driven cancer comprising administering to said subject an agent targeting the extracellular production of adenosine and / or an agent antagonizing the activation by adenosine of one of its receptors.

Description

(19) *EP004660628A3* (11) EP 4 660 628 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 21.01.2026 Bulletin 2026 / 04 (43) Date of publication A2: 10.12.2025 Bulletin 2025 / 50 (21) Application number: 25201893.2 (22) Date of filing: 11.03.2020 (51) International Patent Classification (IPC): A61K 31 / 506 (2006.01) A61K 31 / 519 (2006.01) A61K 38 / 00 (2006.01) A61K 39 / 00 (2006.01) A61K 39 / 39 (2006.01) A61P 35 / 00 (2006.01) A61K 31 / 555 (2006.01) A61K 31 / 675 (2006.01) A61K 31 / 704 (2006.01) A61K 31 / 7076 (2006.01) A61K 33 / 24 (2019.01) A61K 45 / 06 (2006.01) C07K 16 / 28 (2006.01) G01N 33 / 50 (2006.01) (52) Cooperative Patent Classification (CPC): (C-Sets available) A61K 31 / 506; A61K 31 / 519; A61K 31 / 555; A61K 31 / 675; A61K 31 / 704; A61K 31 / 7076; A61K 33 / 24; A61K 45 / 06; A61P 35 / 00; G01N 33 / 5011; A61K 2039 / 505; C07K 16 / 2818 (Cont.) (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 12.03.2019 US 201962817425 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 20770898.3 / 3 937 964 (71) Applicant: Arcus Biosciences, Inc. Hayward, CA 94545 (US) (72) Inventors: • TAN, Joanne B.L. San Francisco, 94110 (US) • UDYAVAR, Akshata R. Foster City, 94404 (US) • YOUNG, Steve W. Palomar Park, 94062 (US) (74) Representative: Müller, Christian Stefan Gerd ZSP Patentanwälte PartG mbB Hansastraße 32 80686 München (DE) (54) TREATMENT OF ONCOGENE‑DRIVEN CANCERS (57) The present disclosure provides methods of treating a subject identified as having an oncogene dri- ven cancer comprising administering to said subject an agent targeting the extracellular production of adenosine and / oranagentantagonizing theactivationbyadenosine of one of its receptors. EP 4 66 0 62 8 A 3 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) (52) Cooperative Patent Classification (CPC): (Cont.) C-Sets A61K 31 / 506, A61K 2300 / 00; A61K 31 / 519, A61K 2300 / 00; A61K 31 / 555, A61K 2300 / 00; A61K 31 / 675, A61K 2300 / 00; A61K 31 / 704, A61K 2300 / 00; A61K 31 / 7076, A61K 2300 / 00; A61K 33 / 24, A61K 2300 / 00 2 EP 4 660 628 A3 3 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 4 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 5 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 6 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 7 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 8 EP 4 660 628 A3 5 10 15 20 25 30 35 40 45 50 55 摘要 摘要 本公开文本提供了治疗被鉴定为患有致癌基因驱动的癌症的的受试者的方法，所述方法包括 向所述受试者施用靶向腺苷的细胞外产生的药剂；和 / 或拮抗腺苷对其受体之一的激活的药 剂。

Claims

1. An agent antagonizing the activation by adenosine of one of its receptors for use in treating an oncogene driven cancer having a mutation in at least one gene selected from the group consisting of KRAS and EGFR in a human subject identified as having said mutation in said cancer; wherein the agent antagonizing the activation by adenosine of one of its receptors is an adenosine A2a receptor (A2aR) and / or adenosine A2b receptor (A2bR) antagonist having the Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein, G1 is N or CR3a; G2 is N or CR3b; G3 is N or CR3c; R3a, R3b, and R3c are each independently H or C1-3 alkyl; R1a and R1b are each independently selected from the group consisting of i) H, ii) C1-8 alkyl optionally substituted with from 1-3 R5 substituents, iii) -X1-O-C1-8 alkyl optionally substituted with from 1-3 R5 substituents, iv) -C(O)-R6, v) Y optionally substituted with 1-3 R7 substituents, and vi) -X1-Y optionally substituted with 1-3 R7 substituents; or vii) R1a and R1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with from 1-3 R8 substituents, wherein the heterocycloalkyl has 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S; each Y is C3-8 cycloalkyl or 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S; R2 and R4 are each independently H or C1-3 alkyl; Ar1 is phenyl or a 5 to 6-membered heteroaryl, each of which is optionally substituted with 1-3 R9; Ar2 is phenyl or a 5 to 6-membered heteroaryl, each of which is optionally substituted with 1-3 R10; wherein the 5 to 6-membered heteroaryl of Ar1 and Ar2 each independently have 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S; each X1 is C1-6 alkylene; each R5 is independently selected from the group consisting of hydroxyl, C3-8 cycloalkyl, phenyl, -O-phenyl, -C(O)ORa and oxo; each R6 is C1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, -O-phenyl, phenyl, and -O-C1-8 alkyl; each R7 is independently selected from the group consisting of C1-8 alkyl, hydroxyl, -O-C1-8 alkyl, oxo, and C(O)ORa; each R8 is independently selected from the group consisting of C1-8 alkyl, hydroxyl, and oxo; each R9 is independently selected from the group consisting of C1-8 alkyl, -O-C1-8 alkyl, -X1-O-C1-8 alkyl, -O-X1-O-C1-8 alkyl, -X1-O-X1-O-C1-8 alkyl, -C(O)ORa, halogen, cyano, -NRbRc, Y, -X1-C3-8 cycloalkyl, and -X2-Z, wherein X2 is selected from the group consisting of C1-6 alkylene, -C1-6 alkylene-O-, -C(O)-, and -S(O)2-, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each of said R9 substituents is optionally substituted with 1-3 R11; each R10 is independently selected from the group consisting of C1-8 alkyl, halo, cyano, -O-C1-8 alkyl, -X1-O-C1-8 alkyl, -O-X1-O-C1-8 alkyl, -S(O)2-C1-6 alkyl, -C(O)NRdRe, and 4-6-membered heteroaryl having from 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each of said R10 substituents is optionally substituted with 1-3 R12, or two R10 on adjacent ring vertices of Ar2 are optionally combined to form a 5-membered heterocyclic ring optionally substituted with 1-2 halogens; each R11 is independently selected from the group consisting of hydroxyl, halo, cyano, -NRdRe, -C(O)ORa, phenyl, C3-8 cycloalkyl, and C1-4 alkyl optionally substituted with C(O)ORa; each R12 is independently selected from the group consisting of halo, cyano, hydroxy, -C(O)ORa; and each Ra is H or C1-6 alkyl; each Rb and Rc are independently selected from the group consisting of H, C1-8 alkyl, -S(O)2-C1-6 alkyl, -C(O)ORa, and -X1-C(O)ORa; each Rd and Re are independently selected from the group consisting of H, C1-8 alkyl, -S(O)2-C1-6 alkyl; and provided that when G1 and G2 are each N, G3 is CH, R2 is CH3, and R1a and R1b are each H, then Ar2 is other than 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl or 2- or 4-methylphenyl.

2. The agent for use according to claim 1, wherein the adenosine A2a receptor (A2aR) or adenosine A2b receptor (A2bR) antagonist is Compound 1 or a pharmaceutically acceptable salt thereof; or Compound 2 or a pharmaceutically acceptable salt thereof; or Compound 3 or a pharmaceutically acceptable salt thereof.

3. The agent for use according to claim 1 or 2, wherein the subject identified as having an oncogene driven cancer has a mutation in the KRAS gene.

4. The agent for use according to any one of claims 1 to 3, further comprising one or more additional therapeutic agents.

5. The agent for use according to claim 4, wherein the additional therapeutic agent is selected from (i) an immune checkpoint inhibitor that blocks the activity of at least one of PD1, PDL1, BTLA, LAG3, a B7 family member, TIM3, TIGIT or CTLA4, and (ii) a chemotherapeutic agent.

6. The agent for use according to any one of claims 1 to 5, wherein the oncogene driven cancer is a cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin, mesothelial lining, white blood cell, esophagus, breast, muscle, connective tissue, lung, adrenal gland, thyroid, kidney, or bone; or is glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, or testicular seminoma.

7. The agent for use according to any one of claims 1 to 6, wherein the oncogene driven cancer is a cancer of the thyroid, adrenal gland, mesothelial lining, bile duct, pancreas, brain, kidney, esophagus, rectum, colon, stomach, head, neck, skin, testis, ovary, lung, endometrium, eye, prostate, breast, or liver; or is glioblastoma, mesothelioma or sarcoma.

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