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1. WO2020112672 - BIOMARQUEURS PRÉDICTIFS D'UNE RÉPONSE DE CELLULE CANCÉREUSE AU TRAITEMENT PAR ML329 OU UN DÉRIVÉ DE CELUI-CI

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[ EN ]

What is claimed is:

1. A method of identifying the likelihood of reducing hyperproliferation of a cancer cell contacted with ML329 or a derivative thereof, the method comprising:

a) obtaining or providing a sample comprising cancer cell;

b) measuring the presence, copy number, amount, and/or activity of i) at least one biomarker listed in Table 1 A and/or ii) at least one biomarker listed in Table IB in the sample; and

c) comparing the presence, copy number, amount, and/or activity of i) the at least one biomarker listed in Table 1 A and/or ii) the at least one biomarker listed in Table IB in a control,

wherein the absence of or a significantly decreased amount or activity of the at least one biomarker listed in Table 1 A in the sample and/or the presence of or a significantly increased amount or activity of the at least one biomarker listed in Table IB thereof in the sample relative to the control sample identifies the cancer cell as being less likely to be responsive to ML329 or a derivative thereof; or wherein the presence of or a significantly increased amount or activity of the at least one biomarker listed in Table 1 A in the subject sample and/or the absence of or a decreased amount or activity of the at least one biomarker listed in Table IB in the sample relative to the control sample identifies the cancer cell as being more likely to be responsive to ML329 or a derivative thereof.

2. The method of claim 1, further comprising contacting the cancer cell with ML329 or the derivative thereof if the cancer cell is determined likely to be responsive to ML329 or the derivative thereof or contacting the cancer cell with an anti-cancer therapy other than ML329 or the derivative thereof as a single agent if the cancer cell is determined to be less likely to be responsive to ML329 or the derivative thereof.

3. The method of claim 2, wherein the anti-cancer therapy other than ML329 or the derivative thereof as a single agent comprises ML329 or the derivative thereof.

4. The method of any one of claims 1-3, wherein the anti-cancer therapy is selected from the group consisting of targeted therapy, chemotherapy, radiation therapy, and/or hormonal therapy.

5. The method of any one of claims 2-4, wherein the anti-cancer therapy contacts the cancer cell in combination with ML329 or the derivative thereof, optionally wherein the anti-cancer therapy contacts the cancer cell before, after, or concurrently with ML329 or the derivative thereof.

6. The method of claim 4, wherein the targeted therapy is an immunotherapy.

7. The method of claim 6, wherein the immunotherapy is cell-based.

8. The method of claim 6, wherein the immunotherapy comprises a cancer vaccine and/or virus.

9. The method of any one of claims 1-8, wherein the immunotherapy inhibits an immune checkpoint.

10. The method of claim 9, wherein the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-ffiB, OX-40, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1,

B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilins, and A2aR.

11. The method of claim 10, wherein the immune checkpoint is PD-1, PD-L1, or CTLA-4.

12. The method of any one of claims 1-11, wherein the contacting occurs in vivo , ex vivo , or in vitro.

13. The method any one of claims 1-12, wherein the cancer cell has a KEAPl loss-of-function mutation.

14. The method of any one of claims 1-13, wherein the KEAPl loss-of-function mutation is a coding region mutation, or a mutation at the corresponding amino acid in the human KEAPl protein or ortholog thereof.

15. The method of any one of claims 1-14, wherein the cancer is selected from the group consisting of melanoma, lung cancer, head and neck squamous cell carcinomas,

kidney cancer, pancreas cancer, prostate cancer, bladder cancer, uterine cancer, head and neck cancer, and esophagus cancer.

16. The method of any one of claims 1-15, wherein the sample is from a subject afflicted with cancer.

17. The method of claim 16, wherein the control is determined from a cancerous or non-cancerous sample from a subject.

18. The method of claim 16, wherein the control is determined from a cancerous or non-cancerous sample from a member of the same species to which the subject belongs.

19. The method of any one of claims 1-18, wherein the control is a reference value.

20. The method of any one of claims 1-18, wherein the control comprises cells, optionally wherein the cells are cancer cells.

21. The method of claim 20, wherein the control sample comprises cancer cells that are responsive to ML329 or the derivative thereof.

22. A method of assessing the efficacy of ML329 or a derivative thereof for treating a cancer in a subject or prognosing progression of a cancer in a subject, comprising:

a) detecting in a subject sample comprising cancer cells at a first point in time the presence, copy number, amount, and/or activity of i) at least one biomarker listed in Table 1 A and/or ii) at least one biomarker listed in Table IB;

b) repeating step a) during at least one subsequent point in time after administration of ML329 or the derivative thereof; and

c) comparing the presence, copy number, amount, and/or activity of i) the at least one biomarker listed in Table 1 A and/or ii) the at least one biomarker listed in Table IB from steps a) and b),

wherein the absence of or a significantly decreased amount or activity of i) the at least one biomarker listed in Table 1 A and/or ii) the at least one biomarker listed in Table IB in the cancer cells of the subsequent sample, relative to the sample at the first point in time, indicates that ML329 or the derivative thereof does not treat the cancer in the subject; and wherein the presence of or a significantly increased amount or activity of i) the at least one biomarker listed in Table 1 A and/or ii) the at least one biomarker listed in Table IB in the subsequent sample, relative to the sample at the first point in time, indicates that ML329 or the derivative thereof treats the cancer in the subject.

23. The method of claim 22, wherein between the first point in time and the subsequent point in time, the subject has undergone treatment, completed treatment, and/or is in remission for the cancer.

24. The method of claim 22 or 23, wherein the first and/or at least one subsequent sample is selected from the group consisting of ex vivo and in vivo samples.

25. The method of any one of claims 22-24, wherein the first and/or at least one subsequent sample is obtained from an animal model of the cancer.

26. The method of any one of claims 21-25, wherein the first and/or at least one subsequent sample is a portion of a single sample or pooled samples obtained from the subject.

27. The method of any one of claims 1-26, wherein the sample comprises cells, cell lines, histological slides, paraffin embedded tissue, fresh frozen tissue, fresh tissue, biopsies, blood, plasma, serum, buccal scrape, saliva, cerebrospinal fluid, urine, stool, mucus, bone marrow, peritumoral tissue, and/or intratumoral tissue obtained from the subject.

28. The method of any one of claims 1-27, further comprising determining

responsiveness to ML329 or the derivative thereof by measuring at least one criteria selected from the group consisting of clinical benefit rate, survival until mortality, pathological complete response, semi -quantitative measures of pathologic response, clinical complete remission, clinical partial remission, clinical stable disease, recurrence-free survival, metastasis free survival, disease free survival, circulating tumor cell decrease, circulating marker response, and RECIST criteria.

29. The method of any one of claims 21-28, further comprising recommending, prescribing, or administering ML329 or the derivative thereof to the subject if ML329 or the derivative thereof is determined to treat the cancer in the subject.

30. The method of any one of claims 21-28, further comprising recommending, prescribing, or administering a therapy other than ML329 or the derivative thereof as a single agent to the subject if ML329 or the derivative thereof is determined not to treat the cancer in the subject.

31. A cell-based assay for screening for anti-CK2 agents that have a selective cytotoxic or cytostatic effect on cancer cells expressing i) at least one biomarker listed in Table 1 A and/or ii) at least one biomarker listed in Table IB comprising contacting the cancer cells with an anti-CK2 test agent, and determining the ability of the test agent to reduce the viability or proliferation of the cancer cells relative to control cancer cells that express reduced or none of i) the at least one biomarker listed in Table 1 A and/or ii) the at least one biomarker listed in Table IB.

32. The method of claim 31, wherein the control is determined from a cancerous or non-cancerous sample from a subject or a member of the same species to which the subject belongs.

33. The method of claim 31 or 32, wherein the control is a reference value.

34. The method of any one of claims 31-33, wherein the control sample comprises cancer cells lacking functional NQOl and/or cancer cells that are not responsive to ML329 or a derivative thereof.

35. The cell-based assay of any one of claims 31-34, wherein the cancer cell is isolated from an animal model of cancer, or a human patient afflicted with cancer.

36. The cell-based assay of any one of claims 31-35, wherein the step of contacting occurs in vivo , ex vivo , or in vitro.

37. The cell-based assay of any one of claims 31-36, wherein the agent is administered in a pharmaceutically acceptable formulation.

38. The method or assay of any one of claims 21-37, wherein the cancer or the cancer cell has a KEAPl loss-of-function mutation.

39. The method or assay of any one of claims 21-38, wherein the KEAP1 loss-of-function mutation is a coding region mutation, or a mutation at the corresponding amino acid in the human KEAP1 protein or ortholog thereof.

40. The method or assay of any one of claims 21-39, wherein the cancer is selected from the group consisting of melanoma, lung cancer, head and neck squamous cell carcinomas, kidney cancer, pancreas cancer, prostate cancer, bladder cancer, uterine cancer, head and neck cancer, and esophagus cancer..

41. The method or assay of any one of claims 1-40, wherein the ML329 derivative has a Formula:


wherein:

(i) X is CH;

Ri is hydrogen, halogen, optionally substituted heterocycloalkyl, optionally

substituted heteroaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted lower alkyl, amino, optionally substituted alkylamino, optionally substituted dialkylamino, -NHCEbCE^CEb , or CEbCE^CEb;

R2 is optionally substituted lower alkyl, optionally substituted aryl or heteroaryl, optionally substituted benzyl, -C(0)-R4, -S(0)2-R4, or -CH(R5)R4, or - CH2CH=CH2;

R3 is hydrogen, optionally substituted lower alkyl, or acyl;

R4 is optionally substituted aryl or heteroaryl;

R5 is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof,

provided

that compound is not 4-((l,4-dioxo-l,4-dihydronaphthalen-2- yl)amino)benzensulfonamide; or

(ii) X is N;

Ri is hydrogen, halogen, optionally substituted heterocycloalkyl, optionally

substituted heteroaryl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted lower alkyl, amino, optionally substituted alkylamino, optionally substituted dialkylamino, or -NHCH2CH=CH2; R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or heteroaryl, optionally substituted benzyl, -C(0)-R4, -S(0)2-R4, or -CH(Rs)-R4, or - CH2CH=CH2;

R3 is hydrogen, optionally substituted lower alkyl, or acyl;

R4 is optionally substituted aryl or heteroaryl;

R5 is hydrogen or lower alkyl; and pharmaceutically acceptable salts thereof.

42. The method or assay of any one of claims 1-41, wherein:

X is CH;

Ri is hydrogen, halogen, a 5- or 6-membered heterocycloalkyl or heteroaryl (each optionally substituted with lower alkyl or phenyl), alkoxy, phenyl, lower alkyl (optionally substituted with phenyl), -N(CH2CH3)2), -NHCH2CH=CH2, NH2, or - CH2CH=CH2;

R2 is lower alkyl, phenyl (optionally mono- or di-substituted independently with halogen, lower alkyl, -S(0)2NH2 or alkoxy), -CTb-phenyl (said phenyl optionally substituted with halogen), C(0)-phenyl (said phenyl optionally substituted with halogen), S(0)2-phenyl (said phenyl optionally substituted with halogen), S(0)2- thiophenyl (said thiophenyl optionally substituted with halogen), thiophenyl, or - CH2CH=CH2; and

R3 is hydrogen, lower alkyl, or acetyl.

43. The method or assay of any one of claims 1-42, wherein Ri is hydrogen, chlorine, methyl, methoxy, phenyl, piperazinyl, methylpiperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, phenylpiperazinyl, ethyl-piperazinyl, -NHCH2CH=CH2, -CH2CH=CH2, -NH2, tert-butyl-piperazinyl, pyrrolidinyl, -NHCH2CH2CH2N(CH2CH3)2 , -CH2CH2CH2N (CH2CH3)2, or -CH(CH3)phenyl.

44. The method or assay of any one of claims 1-43, wherein R2 is methyl, -CH2CH=CH2, phenyl, -CTb-chlorophenyl, chlorophenyl, acetyl, -C(0)-phenyl, -C(O)-bromophenyl, -S(0)2-phenyl, -S(0)2-bromophenyl, -S(0)2-thiazolyl, -S(0)2-bromothiazolyl, difluorophenyl, methoxyphenyl or -phenyl-S(0)2NH2.

45. The method or assay of any one of claims 1-44, wherein R3 is hydrogen, methyl or acetyl.

46. The method or assay of any one of claims 1-45, wherein:

X is CH;

Ri is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl), or a lower alkyl (optionally substituted with -N(CH2CH3)2);

R2 is methyl; and

R3 1S acetyl.

47. The method or assay of any one of claims 1-46, wherein:

X is CH;

Ri is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl or phenyl), or NH2;

R2 is -C(0)R4;

R3 is H; and

R4 is a phenyl, optionally substituted with a halogen.

48. The method or assay of any one of claims 1-47, wherein:

X is CH;

Ri is a hydrogen, alkoxy, NH2 , or a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl);

R2 is -S(0)2-R4;

R3 is H; and

R4 is a phenyl or thiophenyl, each of which can be optionally substituted with

halogen.

49. The method or assay of any one of claims 1-48, wherein:

X is CH;

Ri is a 5- or 6-membered heterocycloalkyl (optionally substituted with lower alkyl or phenyl);

R2 is a phenyl, optionally substituted with one or two independently selected

substituents from the group consisting of halogen and alkoxy; and

R3 is H.

DFS-27025

50. The method or assay of any one of claims 1-49, wherein:

X is N

Ri is hydrogen, halogen, a 5- or 6-membered heterocycloalkyl or heteroaryl

(optionally substituted with lower alkyl or phenyl), alkoxy, lower alkyl

(optionally substituted with phenyl or -N(CH2CH3)2), or NTk;

R2 is lower alkyl, phenyl (optionally mono- or di-substituted independently with halogen, lower alkyl, -S(0)2NH2 or alkoxy), CTk-phenyl (said phenyl optionally substituted with halogen, C(0)-phenyl (said phenyl optionally substituted with halogen), S(0)2 -phenyl (said phenyl optionally substituted with halogen), S(0)2- thiophenyl (said thiophenyl optionally substituted with halogen), or thiophenyl; and pharmaceutically acceptable salts thereof.

51. The method or assay of any one of claims 1-50, wherein the compound is selected from the group consisting of:


DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025

DFS-27025


DFS-27025

DFS-27025


DFS-27025

DFS-27025


52. The method or assay of any one of claims 1-51, wherein ML329 or a derivative thereof is ML329, CX4945, SCAP105461, or SCAP105463.

53. The method or assay of any one of claims 1-52, wherein the subject is an animal model of cancer.

54. The method or assay of claim 53, wherein the animal model is a rodent model.

55. The method or assay of any one of claims 1-54, wherein the subject is a mammal.

56. The method or assay of claim 55, wherein the mammal is a mouse or a human.

57. The method or assay of claim 56, wherein the mammal is a human.