Methods of Treating Cancer

• US 20140128393A1
• Filed: 10/15/2013
• Published: 05/08/2014
• Est. Priority Date: 10/15/2012
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Knutson, Sarah K., Warholic, Natalie, Keilhack, Heike
• Granted Patent: US 9,688,665 B2
• Time in Patent Office: Days
• US Class Current: 514/235.5
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 211/86 Oxygen atoms
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574

Abstract

The present invention relates to methods of treating cancer by administering the EZH2 inhibitor compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

Claims

1. A method for treating or alleviating a symptom of a SWI/SNF-associated cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of an EZH2 inhibitor, wherein the subject has a cancer selected from the group consisting of brain and central nervous system cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer.

2. The method of claim 1, wherein the SWI/SNF-associated cancer is characterized by reduced expression or loss of function of the SWI/SNF complex or one or more components of the SWI/SNF complex.

3. The method of claim 1, wherein the subject has a cancer selected from the group consisting of medulloblastoma, malignant rhabdoid tumor and atypical teratoid/rhabdoid tumor.

4. The method of claim 2, wherein the one or more components are selected from the group consisting of SNF5, ATRX and ARID1A.

5. The method of claim 2, wherein the loss of function is caused by a loss of function mutation resulting from a point mutation, a deletion and/or an insertion.

6. The method of claim 1, wherein the subject has a deletion of SNF5.

7. The method of claim 1, wherein the subject has a mutation of ATRX selected from the group consisting of a substitution of asparagine (N) for the wild type residue lysine (K) at amino acid position 688 of SEQ ID NO:

5 (K688N), and a substitution of isoleucine (I) for the wild type residue methionine (M) at amino acid position 366 of SEQ ID NO;

5 (M366I).

8. The method of claim 1, wherein said subject has a mutation of ARID1A selected from the group consisting of a nonsense mutation for the wild type residue cysteine (C) at amino acid position 884 of SEQ ID NO:

11 (C884*), a substitution of lysine (K) for the wild type residue glutamic acid (E) at amino acid position 966 (E966K), a nonsense mutation for the wild type residue glutamine (Q) at amino acid position 1411 of SEQ ID NO;

11 (Q1411*), a frame shift mutation at the wild type residue phenylalanine (F) at amino acid position 1720 of SEQ ID NO;

11 (F1720fs), a frame shift mutation after the wild type residue glycine (G) at amino acid position 1847 of SEQ ID NO;

11 (G1847fs), a frame shift mutation at the wild type residue cysteine (C) at amino acid position 1874 of SEQ ID NO;

11 (C1874fs), a substitution of glutamic acid (E) for the wild type residue aspartic acid (D) at amino acid position 1957 (D1957E), a nonsense mutation for the wild type residue glutamine (Q) at amino acid position 1430 of SEQ ID NO;

11 (Q1430*), a frame shift mutation at the wild type residue arginine (R) at amino acid position 1721 of SEQ ID NO;

11 (R1721fs), a substitution of glutamic acid (E) for the wild type residue glycine (G) at amino acid position 1255 (G1255E), a frame shift mutation at the wild type residue glycine (G) at amino acid position 284 of SEQ ID NO;

11 (G284fs), a nonsense mutation for the wild type residue arginine (R) at amino acid position 1722 of SEQ ID NO;

11 (R1722*), a frame shift mutation at the wild type residue methionine (M) at amino acid position 274 of SEQ ID NO;

11 (M274fs), a frame shift mutation at the wild type residue glycine (G) at amino acid position 1847 of SEQ ID NO;

11 (G1847fs), a frame shift mutation at the wild type residue P at amino acid position 559 of SEQ ID NO;

11 (P559fs), a nonsense mutation for the wild type residue arginine (R) at amino acid position 1276 of SEQ ID NO;

11 (R1276*), a frame shift mutation at the wild type residue glutamine (Q) at amino acid position 2176 of SEQ ID NO;

11 (Q2176fs), a frame shift mutation at the wild type residue histidine (H) at amino acid position 203 of SEQ ID NO;

11 (H203fs), a frame shift mutation at the wild type residue alanine (A) at amino acid position 591 of SEQ ID NO;

11 (A591 fs), a nonsense mutation for the wild type residue glutamine (Q) at amino acid position 1322 of SEQ ID NO;

11 (Q1322*), a nonsense mutation for the wild type residue serine (S) at amino acid position 2264 of SEQ ID NO;

11 (S2264*), a nonsense mutation for the wild type residue glutamine (Q) at amino acid position 586 of SEQ ID NO;

11 (Q586*), a frame shift mutation at the wild type residue glutamine (Q) at amino acid position 548 of SEQ ID NO;

11 (Q548fs), and a frame shift mutation at the wild type residue asparagine (N) at amino acid position 756 of SEQ ID NO;

11 (N756fs).

33. The method of claim 1, wherein the EZH2 inhibitor is:

34. The method of claim 1, wherein the EZH2 inhibitor is:

9. A method of treating or alleviating a symptom of a SWI/SNF-associated cancer in a subject in need thereof comprising:

a. determining the expression level of at least one gene selected from the group consisting of neuronal differentiation genes, cell cycle inhibition genes and tumor suppressor genes in a sample obtained from the subject;

b. selecting a subject having a decreased expression level of at least one gene in step a; and

c. administering to the subject selected in step b an effective amount of an EZH2 inhibitor, thereby treating or alleviating a symptom of cancer in the subject.

11. The method of claim 9, wherein the cancer is selected from the group consisting of medulloblastoma, malignant rhabdoid tumor, and atypical teratoid rhabdoid tumor.

13. The method of claim 9, wherein the neuronal differentiation gene is CD133, DOCK4, or PTPRK.

14. The method of claim 9, wherein the cell cycle inhibition gene is CKDN1A or CDKN2A.

15. The method of claim 9, wherein the tumor suppressor gene is BIN1.

10. A method of treating or alleviating a symptom of a SWI/SNF-associated cancer in a subject in need thereof comprising:

a. determining the expression level of at least one gene selected from the group consisting of hedgehog pathway genes, myc pathway genes and histone methyltransferase genes in a sample obtained from the subject,

b. selecting a subject having an increased expression level of at least one gene in step a; and

c. administering to the subject selected in step b an effective amount of an EZH2 inhibitor, thereby treating or alleviating a symptom of cancer in the subject.

12. The method of claim 10, wherein the cancer is selected from the group consisting of medulloblastoma, malignant rhabdoid tumor, and atypical teratoid rhabdoid tumor.

16. The method of claim 10, wherein the hedgehog pathway gene is GLI1 or PTCH1.

17. The method of claim 10, wherein the myc pathway gene is MYC.

18. The method of claim 10, wherein the histone methyltransferase gene is EZH2.

19. A method of inducing neuronal differentiation, cell cycle inhibition or tumor suppression comprising contacting a cell with an EZH2 inhibitor.

20. The method of claim 19, wherein the EZH2 inhibitor is in an amount sufficient to increase expression of at least one gene selected from the group consisting of CD133, DOCK4,PTPRK, CKDN1A,CDKN2A, and BIN1.

29. The method of claim 19, wherein the cell comprises loss of function of SNF5, ARID1A, ATRX, and/or a component of the SWI/SNF complex.

30. The method of claim 29, wherein the loss of function is caused by a deletion of SNF5.

31. The method of claim 19, wherein the cell is a cancer cell.

32. The method of claim 31, wherein the cancer is selected from the group consisting of medulloblastoma, malignant rhabdoid tumor, and atypical teratoid rhabdoid tumor.

21. A method of inhibiting hedgehog signaling comprising contacting a cell with an EZH2 inhibitor.

22. The method of claim 21, wherein the EZH2 inhibitor is in an amount sufficient to reduce expression of GLI1 and/or PTCH1.

23. A method of inducing gene expression comprising contacting a cell with an EZH2 inhibitor.

24. The method of claim 23, wherein the EZH2 inhibitor is in an amount sufficient to induce neuronal differentiation, cell cycle inhibition and/or tumor suppression.

25. The method of claim 23, wherein the gene is selected from the group consisting of CD133, DOCK4, PTPRK, CKDN1A, CKDN2A, and BIN1.

26. A method of inhibiting gene expression comprising contacting a cell with an EZH2 inhibitor.

27. The method of claim 26, wherein the EZH2 inhibitor is in an amount sufficient to inhibit hedgehog signaling.

28. The method of claim 26, wherein the gene is GLI1 or PTCH1.