HEMATOPOIETIC PROTECTION AGAINST CHEMOTHERAPEUTIC COMPOUNDS USING SELECTIVE CYCLIN-DEPENDENT KINASE 4/6 INHIBITORS
First Claim
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.
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Accused Products
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.
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Citations
49 Claims
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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:
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(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. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 17, 20, 25, 42, 43, 44, 45, 46, 47, 48, 49)
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2-7. -7. (canceled)
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16. (canceled)
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18-19. -19. (canceled)
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21-24. -24. (canceled)
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26-41. -41. (canceled)
Specification