Method of treating cancer with nucleotide therapeutics

Patent metadata

Field	Value
Publication number	US-2022249534-A1
Application number	US-202217650298-A
Country	US
Kind code	A1
Filing date	Feb 8, 2022
Priority date	Feb 11, 2021
Publication date	Aug 11, 2022
Grant date	—

Abstract

The present disclosure provides methods for inhibiting cell proliferation, inducing differentiation, and inducing replication stress in a cancer cell. The present disclosure also provides methods for treating a cancer in a patient. Various methods of the disclosure include contacting a cancer cell with, or administering to a patient having cancer, an agent that can change the internal baseline ratio of purine:pyrimidine in the cancer cell.

First claim

1 . A method of inhibiting proliferation in a cancer cell, the cancer cell having an endogenous baseline ratio of purine:pyrimidine, the method comprising:
contacting the cell with an agent in an amount sufficient to change the endogenous baseline ratio of purine:pyrimidine in the cell, resulting in a nucleotide imbalance, the agent comprising a purine, a purine precursor, a purine analog that is not a purine biosynthesis inhibitor, a pyrimidine, a pyrimidine precursor, and/or a pyrimidine analog that is not a pyrimidine biosynthesis inhibitor, the nucleotide imbalance inhibiting the cancer cell from proliferating.

2 . The method of claim 1 , wherein the agent is a purine nucleotide.

3 . The method of claim 2 , wherein the purine nucleotide is Adenine or Guanine.

4 . The method of claim 1 , wherein the agent is Adenine.

5 . The method of claim 1 , wherein the agent is a purine precursor.

6 . The method of claim 5 , wherein the purine precursor is AIR, CAIR, SACAIR, AICAR, FAICAR inosine mono phosphate (IMP), adenylosuccinate, xanthine, or hypoxanthine.

7 . The method of claim 1 , wherein the agent is a purine analog that does not inhibit purine biosynthesis.

8 . The method of claim 7 , wherein the purine analog is 8-amino-adenosine.

9 . The method of claim 1 , wherein the cancer cell is contacted with at least one purine and at least one purine precursor.

10 . The method of claim 9 , wherein the cancer cell is further contacted with at least on purine analog that is not an inhibitor of purine biosynthesis.

11 . The method of claim 1 , further comprising contacting the cancer cell with a pyrimidine biosynthesis inhibitor.

12 . The method of claim 11 , wherein the pyrimidine biosynthesis inhibitor is mercaptopurine, 6-mercaptopurine, mycophenolic acid, mycophenolate mofetil, 6-thioguanine, lometrexol, pyrimethamine, or cladribine.

13 . The method of claim 1 , wherein the agent is a pyrimidine nucleotide.

14 . The method of claim 13 , wherein the pyrimidine nucleotide is Cytosine, Thymidine, or Uracil.

15 . The method of claim 1 , wherein the agent is a pyrimidine precursor.

16 . The method of claim 15 , wherein the pyrimidine precursor is dihydroorotate, orotate, uracil monophosphate (UMP), UDP, CMP, or CDP.

17 . The method of claim 1 , wherein the agent is a pyrimidine analog that does not inhibit pyrimidine biosynthesis.

18 . The method of claim 17 , wherein the pyrimidine analog is cytarabine, nalarabine, sapacitabine, ARC (4-amino-6-hydrazino-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide).

19 . The method of claim 1 , wherein the cancer cell is contacted with at least one pyrimidine and at least one pyrimidine precursor.

20 . The method of claim 19 , wherein the cancer cell is further contacted with at least on pyrimidine biosynthesis inhibitor that is not a pyrimidine biosynthesis inhibitor.

21 . The method of claim 1 , further comprising contacting the cancer cell with a purine biosynthesis inhibitor.

22 . The method of claim 21 , wherein the purine biosynthesis inhibitor is Azathioprine, Mercaptopurine, Clofarabine, Thioguanine, Fludarabine, Pentostatin, Cladribine or Acycloguanosine.

23 . The method of claim 1 , further comprising contacting the cells with a pyrimidine biosynthesis inhibitor.

24 . The method of claim 23 , wherein the pyrimidine biosynthesis inhibitor is brequinar, leflunomide, teriflunomide, pyrazofurin, cyclopentenyl cytosine, fluorocyclopentenylcytosine, 5-fluorouracil, ralitrexed, pemetrexed, or 6-azauridine.

25 . The method of claim 1 , wherein the cancer cell is a liquid cancer cell or a solid cancer cell.

26 . A method of inducing differentiation in a cancer cell, the cancer cell having an endogenous baseline ratio of purine:pyrimidine, the method comprising:
contacting the cell with an agent in an amount sufficient to change the endogenous baseline ratio of purine:pyrimidine in the cell, resulting in a nucleotide imbalance, the agent comprising a purine, a purine precursor, a purine analog that is not a purine biosynthesis inhibitor, a pyrimidine, a pyrimidine precursor, and/or a pyrimidine analog that is not a pyrimidine biosynthesis inhibitor, the nucleotide imbalance inducing differentiation in the cancer cell.

27 . The method of claim 26 , wherein the agent is a purine nucleotide.

28 . The method of claim 27 , wherein the purine nucleotide is Adenine or Guanine.

29 . The method of claim 28 , wherein the agent is Adenine.

30 . The method of claim 26 , wherein the agent is a purine precursor.

31 . The method of claim 30 , wherein the purine precursor is AIR, CAIR, SACAIR, AICAR, FAICAR inosine mono phosphate (IMP), adenylosuccinate, xanthine, or hypoxanthine.

32 . The method of claim 26 , wherein the agent is a purine analog that is not a purine biosynthesis inhibitor.

33 . The method of claim 32 , wherein the purine analog is 8-amino-adenosine.

34 . The method of claim 26 , wherein the cancer cell is contacted with at least one purine and at least one purine precursor.

35 . The method of claim 34 , wherein the cancer cell is further contacted with at least on purine analog that is not an inhibitor of purine biosynthesis.

36 . The method of claim 26 , further comprising contacting the cancer cell with a pyrimidine biosynthesis inhibitor.

37 . The method of claim 36 , wherein the pyrimidine biosynthesis inhibitor is mercaptopurine, 6-mercaptopurine, mycophenolic acid, mycophenolate mofetil, 6-thioguanine, lometrexol, pyrimethamine, or cladribine.

38 . The method of claim 26 , wherein the agent is a pyrimidine nucleotide.

39 . The method of claim 38 , wherein the pyrimidine nucleotide is Cytosine, Thymidine, or Uracil.

40 . The method of claim 27 wherein the agent is a pyrimidine precursor.

41 . The method of claim 40 , wherein the pyrimidine precursor is dihydroorotate, orotate, uracil monophosphate (UMP), UDP, CMP, or CDP.

42 . The method of claim 26 , wherein the agent is a pyrimidine analog that is not an inhibitor of pyrimidine biosynthesis.

43 . The method of claim 42 , wherein the pyrimidine analog is cytarabine, nalarabine, sapacitabine, ARC (4-amino-6-hydrazino-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide).

44 . The method of claim 26 , wherein the cancer cell is contacted with at least one pyrimidine and at least one pyrimidine precursor.

45 . The method of claim 44 , wherein the cancer cell is further contacted with at least on pyrimidine analog that is not an inhibitor of pyrimidine biosynthesis.

46 . The method of claim 26 , further comprising contacting the cell with a purine biosynthesis inhibitor.

47 . The method of claim 46 , wherein the purine biosynthesis inhibitor is Azathioprine, Mercaptopurine, Clofarabine, Thioguanine, Fludarabine, Pentostatin, Cladribine, or Acycloguanosine.

48 . The method of claim 26 , further comprising contacting the cancer cell with a pyrimidine biosynthesis inhibit

Assignees

• Massachusetts Inst Technology
• Massachusetts Gen Hospital

Inventors

• Vander Heiden Matthew G
• Hsu Peggy P
• Diehl Frances Flewelling
• Sykes David B

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title