Transient protection of normal cells during chemotherapy
This invention is in the area of improved compounds, compositions and methods of transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, improved protection of healthy cells is disclosed using disclosed compounds that act as highly selective and short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.
1. A method of reducing the effect of chemotherapy on healthy cells in a subject being treated for cyclin-dependent kinase 4/6 (CDK4/6) replication independent cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells, hematopoietic progenitor cells, or renal epithelial cells, the method comprising administering to the subject an effective amount of at least one chemotherapeutic agent and a compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the subject is a human.
3. The method of claim 2 , wherein the subject has cancer.
4. The method of claim 2 , wherein the subject has an abnormal cell proliferation.
5. The method of claim 2 , wherein the cancer or abnormal cell proliferation is characterized by a loss or absence of retinoblastoma tumor suppressor protein (RB).
6. The method of claim 2 , wherein the cancer is small cell lung cancer, retinoblastoma, triple negative breast cancer, human papillomavirus (HPV) positive head and neck cancer, HPV positive cervical cancer, or bladder cancer.
7. The method of claim 6 , wherein the cancer is small cell lung carcinoma.
8. The method of claim 2 , wherein the at least one chemotherapeutic agent is an alkylating agent, DNA intercalator, protein synthesis inhibitor, inhibitor of DNA or RNA synthesis, DNA base analog, topoisomerase inhibitor, telomerase inhibitor, or a telomeric DNA binding compound.
9. The method of claim 2 , wherein at least 80% or more of the hematopoietic stem cells or hematopoietic progenitor cells re-enter the cell cycle in less than about 36 hours from the last administration of the compound.
10. The method of claim 2 , wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.
11. The method of claim 2 , wherein the healthy cells are renal epithelial cells.
12. The method of claim 2 , wherein the administered compound is
or a pharmaceutically acceptable salt thereof.
13. The method of claim 2 , wherein the administered compound is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 2 , wherein the compound is administered prior to the administration of the at least one chemotherapeutic agent.
15. The method of claim 14 , wherein the compound is administered to the subject about 24 hours or less prior to the administration of the at least one chemotherapeutic agent.
16. The method of claim 2 , wherein the compound is administered concurrently with the administration of the at least one chemotherapeutic agent.
17. The method of claim 2 , wherein the compound is administered subsequently to the administration of the at least one chemotherapeutic agent.
18. The method of claim 2 , wherein the at least one chemotherapeutic agent is cisplatin.
19. The method of claim 2 , wherein the at least one chemotherapeutic agent is carboplatin.
20. The method of claim 2 , wherein the at least one chemotherapeutic agent is topotecan.
21. The method of claim 2 , wherein the at least one chemotherapeutic agent is irinotecan.
22. The method of claim 2 , wherein the at least one chemotherapeutic agent is doxorubicin.
23. The method of claim 2 , wherein the at least one chemotherapeutic agent is paclitaxel.
24. The method of claim 2 , wherein the at least one chemotherapeutic agent is cyclophosphamide.
25. The method of claim 2 , wherein the at least one chemotherapeutic agent is docetaxel.
26. The method of claim 2 , wherein the at least one chemotherapeutic agent is fluorouracil.
27. The method of claim 2 , wherein the at least one chemotherapeutic agent is methotrexate.
28. The method of claim 2 , wherein the at least one chemotherapeutic agent is vinblastine.
29. The method of claim 2 , wherein the at least one chemotherapeutic agent is gemcitabine.
30. The method of claim 15 , wherein the compound is administered about 4 hours or less prior to the administration of the at least one chemotherapeutic agent.
31. The method of claim 7 , wherein the at least one chemotherapeutic agent is etoposide.
32. The method of claim 7 , wherein the at least one chemotherapeutic agent is cisplatin.
33. The method of claim 7 , wherein the at least one chemotherapeutic agent is carboplatin.
34. The method of claim 7 , wherein the at least one chemotherapeutic agent is topotecan.
35. The method of claim 7 , wherein the at least one chemotherapeutic agent is irinotecan.
36. The method of claim 6 , wherein the cancer is triple negative breast cancer.
37. The method of claim 36 , wherein the at least one chemotherapeutic agent is doxorubicin.
38. The method of claim 36 , wherein the at least one chemotherapeutic agent is paclitaxel.
39. The method of claim 36 , wherein the at least one chemotherapeutic agent is cyclophosphamide.
40. The method of claim 6 , wherein the cancer is human papillomavirus (HPV) positive head and neck cancer.
41. The method of claim 40 , wherein the at least one chemotherapeutic agent is cisplatin.
42. The method of claim 40 , wherein the at least one chemotherapeutic agent is carboplatin.
43. The method of claim 40 , wherein the at least one chemotherapeutic agent is paclitaxel.
44. The method of claim 40 , wherein the at least one chemotherapeutic agent is docetaxel.
45. The method of claim 40 , wherein the at least one chemotherapeutic agent is 5-fluorouracil.
46. The method of claim 6 , wherein the cancer is bladder cancer.
47. The method of claim 46 , wherein the at least one chemotherapeutic agent is methotrexate.
48. The method of claim 46 , wherein the at least one chemotherapeutic agent is vinblastine.
49. The method of claim 46 , wherein the at least one chemotherapeutic agent is doxorubicin.
50. The method of claim 46 , wherein the at least one chemotherapeutic agent is cisplatin.
51. The method of claim 46 , wherein the at least one chemotherapeutic agent is gemcitabine.
52. The method of claim 6 , wherein the cancer is HPV positive cervical cancer.
53. The method of claim 6 , wherein the cancer is retinoblastoma.
54. The method of claim 2 , wherein the at least one chemotherapeutic agent is etoposide.