HEMATOPOIETIC PROTECTION AGAINST CHEMOTHERAPEUTIC COMPOUNDS USING SELECTIVE CYCLIN-DEPENDENT KINASE 4/6 INHIBITORS

• US 20150111896A1
• Filed: 09/24/2014
• Published: 04/23/2015
• Est. Priority Date: 10/01/2008
• Status: Abandoned Application

• Current Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Sharpless, Norman Edward, Strum, Jay Copeland, Bisi, John Emerson, Roberts, Patrick Joseph, Ramsey, Matthew R.
• Application Number:
  US14/495,381
• Publication Number:
  US 20150111896A1
• Time in Patent Office: Days
• US Class Current: 514/252.16
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• 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 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4738 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: G01N 2333/4739 Cyclin; Prad 1
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics

Abstract

Methods for reducing or preventing the effects of cytotoxic compounds in healthy cells are provided. The methods relate to the use of selective cyclin-dependent kinase (CDK) 4/6 inhibitors to induce transient quiescence in CDK4/6 dependent cells, such as hematopoietic stem cells and/or hematopoietic progenitor cells. Also described is a method of selecting compounds for reducing or preventing the effects of cytotoxic agents compounds in healthy cells.

Claims

1. A method of reducing the effects of a DNA-damaging cytotoxic compound on healthy cells in a subject being treated for cancer who shall be exposed to the DNA-damaging cytotoxic compound, wherein said healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, the method comprising administering to the subject an effective amount of an inhibitor compound, or a pharmaceutically acceptable salt thereof, prior to exposure to the DNA-damaging cytotoxic compound, wherein the inhibitor compound inhibits cyclin-dependent kinase 4 (CDK4), and wherein the inhibitor compound:

(i) has an IC₅₀ for CDK4 that is at least 6 times lower than the IC₅₀ for CDK2;

(ii) is substantially free of off-target effects other than inhibition of CDK6; and

(iii) does not arrest the growth of the cancer.

8. The method of claim 1, wherein the inhibitor compound is selected from the group consisting of a pyrido[2,3-d]pyrimidine, a triaminopyrimidine, an aryl[a]pyrrolo[3,4-c]carbazole, a nitrogen-containing heteroaryl-substituted urea, a 5-pyrimidinyl-2-aminothiazole, a benzothiadiazine, and an acridinethione.

9. The method of claim 8, wherein the pyrido[2,3-d]pyrimidine is a pyrido[2,3-d]pyrimidin-7-one or a 2-amino-6-cyano-pyrido[2,3-d]pyrimidin-4-one.

10. The method of claim 9, wherein the pyrido[2,3-d]pyrimidin-7-one is a 2-(2′

-pyridyl)amino pyrido[2,3-d]pyrimidin-7-one.

11. The method of claim 10, wherein the pyrido[2,3-d]pyrimidin-7-one is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido-[2,3-d]pyrimidin-7-one.

12. The method of claim 8, wherein the aryl[a]pyrrolo[3,4-c]carbazole is selected from the group consisting of a napthyl[a]pyrrolo[3,4-c]carbazole, an indolo[a]pyrrolo[3,4-c]carbazole, a quinolinyl[a]pyrrolo[3,4-c]carbazole, and an isoquinolinyl[a]pyrrolo[3,4-c]carbazole.

13. The method of claim 12, wherein the aryl[a]pyrrolo[3,4-c]carbazole is 2-bromo-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4]-carbazole-5,6-dione.

14. The method of claim 1, wherein the subject is a mammal.

15. The method of claim 1, wherein the inhibitor compound is administered to the subject by one of the group consisting of oral administration, topical administration, intranasal administration, inhalation, and intravenous administration.

17. The method of claim 1, wherein the inhibitor compound is administered to the subject 24 hours or less prior to exposure to the cytotoxic compound.

20. The method of claim 1, wherein the healthy cells are selected from the group consisting of long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), multipotent progenitors (MPPs), common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-monocyte progenitors (GMPs), and megakaryocyte-erythroid progenitors (MEPs).

25. The method of claim 1, wherein the cancer is characterized by one or more of the group consisting of increased activity of cyclin-dependent kinase 1 (CDK1), increased activity of cyclin-dependent kinase 2 (CDK2), loss or absence of retinoblastoma tumor suppressor protein (RB), high levels of MYC expression, viral protein E7 expression, increased cyclin E and increased cyclin A.

42. The method of claim 25, wherein the cancer is characterized by a loss or absence of retinoblastoma tumor suppressor protein (RB).

43. The method of claim 1, wherein the cancer is small cell lung cancer, retinoblastoma, triple negative breast cancer, HPV positive head and neck cancer, or HPV positive cervical cancer.

44. The method of claim 1, wherein the inhibitor compound has an IC₅₀ for CDK4 that is at least 8 times lower than the IC₅₀ for CDK2.

45. The method of claim 1, wherein the inhibitor compound has an IC₅₀ for CDK4 that is at least 10 times lower than the IC₅₀ for CDK2.

46. The method of claim 1, wherein the inhibitor compound has an IC₅₀ for CDK4 that is at least 50 times lower than the IC₅₀ for CDK2.

47. The method of claim 1, wherein the inhibitor compound has an IC₅₀ for CDK4 that is at least 100 times lower than the IC₅₀ for CDK2.

48. The method of claim 1, wherein the DNA-damaging cytotoxic compound is selected from an alkylating agent, DNA intercalator, protein synthesis inhibitor, inhibitor of DNA or RNA synthesis, DNA base analog, topoisomerase inhibitor, telomerase inhibitor or telomeric DNA binding compound.

49. The method of claim 1, wherein the DNA-damaging cytotoxic compound is doxorubicin, etoposide, or carboplatin.

2-7. -7. (canceled)

16. (canceled)

18-19. -19. (canceled)

21-24. -24. (canceled)

26-41. -41. (canceled)