HSPC-sparing treatments for RB-positive abnormal cellular proliferation
This invention is in the area of improved compounds for and methods of treating selected RB-positive cancers and other Rb-positive abnormal cellular proliferative disorders while minimizing the deleterious effects on healthy cells, for example healthy Hematopoietic Stem Cells and Progenitor Cells (HSPCs), associated with current treatment modalities. In one aspect, improved treatment of select RB-positive cancers is disclosed using specific compounds disclosed herein. In certain embodiments, the compounds described herein act as highly selective and, in certain embodiments, short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects.
1. A method for the treatment of a human with cancer, wherein the cancer is Retinoblastoma-positive (Rb) and selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer, and prostate cancer, comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor having the structure:
or a pharmaceutically acceptable salt thereof, and administering to the human an effective amount of a chemotherapeutic agent, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.
2. The method of claim 1 , wherein the cancer is breast cancer.
3. The method of claim 1 , wherein the cancer is colorectal cancer.
4. The method of claim 1 , wherein the cancer is ovarian cancer.
5. The method of claim 1 , wherein the cancer is non-small cell lung cancer.
6. The method of claim 1 , wherein the cancer is prostate cancer.
7. The method of claim 1 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
8. A method for treating a human with Retinoblastoma-positive breast cancer comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor having the structure:
or a pharmaceutically acceptable salt thereof, and administering to the human an effective amount of a chemotherapeutic agent, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.
9. The method of claim 8 , wherein the chemotherapeutic agent is doxorubicin.
10. The method of claim 8 , wherein the chemotherapeutic agent is paclitaxel.
11. The method of claim 8 , wherein the chemotherapeutic agent is carboplatin.
12. The method of claim 8 , wherein the chemotherapeutic agent is gemcitabine.
13. The method of claim 8 , wherein the chemotherapeutic agent is cisplatin.
14. The method of claim 8 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
15. The method of claim 8 , wherein the breast cancer is estrogen-receptor positive.
16. A method for treating a human with Retinoblastoma (Rb)-positive non-small cell lung cancer comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor having the structure
or a pharmaceutically acceptable salt thereof, and administering to the human an effective amount of a chemotherapeutic agent, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.
17. The method of claim 16 , wherein the chemotherapeutic agent is docetaxel.
18. The method of claim 16 , wherein the chemotherapeutic agent is doxorubicin.
19. The method of claim 16 , wherein the chemotherapeutic agent is paclitaxel.
20. The method of claim 16 , wherein the chemotherapeutic agent is etoposide.
21. The method of claim 16 , wherein the chemotherapeutic agent is vinblastine sulfate.
22. The method of claim 16 , wherein the chemotherapeutic agent is carboplatin.
23. The method of claim 16 , wherein the chemotherapeutic agent is gemcitabine.
24. The method of claim 16 , wherein the chemotherapeutic agent is cisplatin.
25. A method for treating a human with Retinoblastoma-positive colorectal cancer comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor having the structure
or a pharmaceutically acceptable salt thereof, and administering to the human an effective amount of a chemotherapeutic agent, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.
26. The method of claim 25 , wherein the chemotherapeutic agent is 5-fluorouracil.
27. The method of claim 25 , wherein the chemotherapeutic agent is capecitabine.
28. The method of claim 25 , wherein the colorectal cancer is metastatic colorectal cancer.
29. The method of claim 25 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
30. The method of claim 1 , wherein the cancer is colorectal cancer.
31. The method of claim 1 , wherein the chemotherapeutic agent is topotecan HC1.
32. The method of claim 1 , wherein the chemotherapeutic agent is docetaxel.
33. The method of claim 1 , wherein the chemotherapeutic agent is doxorubicin.
34. The method of claim 1 , wherein the chemotherapeutic agent is doxorubicin HC1.
35. The method of claim 1 , wherein the chemotherapeutic agent is paclitaxel.
36. The method of claim 1 , wherein the chemotherapeutic agent is etoposide.
37. The method of claim 1 , wherein the chemotherapeutic agent is vinblastine sulfate.
38. The method of claim 1 , wherein the chemotherapeutic agent is carboplatin.
39. The method of claim 1 , wherein the chemotherapeutic agent is gemcitabine.
40. The method of claim 1 , wherein the chemotherapeutic agent is cisplatin.
41. The method of claim 1 , wherein the chemotherapeutic agent is 5-fluorouracil.
42. The method of claim 1 , wherein the chemotherapeutic agent is capecitabine.
43. The method of claim 1 , wherein the chemotherapeutic agent is cyclophosphamide.
44. The method of claim 8 , wherein the chemotherapeutic agent is doxorubicin HC1.
45. The method of claim 8 , wherein the chemotherapeutic agent is cyclophosphamide.
46. The method of claim 8 , wherein the breast cancer is advanced breast cancer.
47. The method of claim 8 , wherein the breast cancer is HER2-negative breast cancer.
48. The method of claim 8 , wherein the breast cancer is HER2-positive breast cancer.
49. The method of claim 8 , wherein the breast cancer is estrogen-receptor negative breast cancer.
50. The method of claim 8 , wherein the breast cancer is estrogen-receptor positive, HER2-negative advanced breast cancer.
51. The method of claim 8 , wherein the breast cancer is progesterone receptor-negative breast cancer.
52. The method of claim 8 , wherein the breast cancer is progesterone receptor-positive breast cancer.
53. The method of claim 16 , wherein the chemotherapeutic agent is topotecan HC1.
54. The method of claim 16 , wherein the chemotherapeutic agent is cyclophosphamide.
55. The method of claim 16 , wherein the chemotherapeutic agent is doxorubicin HC1.
56. The method of claim 16 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
57. A method for the treatment of a human with cancer, wherein the cancer is Retinoblastoma-positive (Rb), comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor having the structure:
or a pharmaceutically acceptable salt thereof, and administering to the human an effective amount of a chemotherapeutic agent, wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.
58. The method of claim 57 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.
59. The method of claim 57 , wherein the Rb-positive cancer is colon cancer.
60. The method of claim 57 , wherein the RB-positive cancer is bladder cancer.
61. The method of claim 57 , wherein the Rb-positive cancer is an adenocarcinoma.
62. The method of claim 57 , wherein the Rb-positive cancer is stomach cancer.
63. The method of claim 57 , wherein the RB-positive cancer is liver cancer.
64. The method of claim 63 , wherein the RB-positive liver cancer is hepatocellular carcinoma.
65. The method of claim 63 , wherein the Rb-positive liver cancer is cholangiocarcinoma.
66. The method of claim 57 , wherein the Rb-positive cancer is pancreatic cancer.
67. The method of claim 57 , wherein the Rb-positive cancer is cancer of the esophagus.
68. The method of claim 57 , wherein the Rb-positive cancer is thyroid cancer.
69. The method of claim 57 , wherein the Rb-positive cancer is kidney cancer.
70. The method of claim 69 , wherein the Rb-positive cancer is renal cell carcinoma.
71. The method of claim 57 , wherein the chemotherapeutic agent is topotecan HC1.
72. The method of claim 57 , wherein the chemotherapeutic agent is docetaxel.
73. The method of claim 57 , wherein the chemotherapeutic agent is doxorubicin.
74. The method of claim 57 , wherein the chemotherapeutic agent is doxorubicin HC1.
75. The method of claim 57 , wherein the chemotherapeutic agent is paclitaxel.
76. The method of claim 57 , wherein the chemotherapeutic agent is etoposide.
77. The method of claim 57 , wherein the chemotherapeutic agent is vinblastine sulfate.
78. The method of claim 57 , wherein the chemotherapeutic agent is carboplatin.
79. The method of claim 57 , wherein the chemotherapeutic agent is gemcitabine.
80. The method of claim 57 , wherein the chemotherapeutic agent is cisplatin.
81. The method of claim 57 , wherein the chemotherapeutic agent is 5-fluorouracil.
82. The method of claim 57 , wherein the chemotherapeutic agent is capecitabine.
83. The method of claim 57 , wherein the chemotherapeutic agent is cyclophosphamide.
84. The method of claim 57 , wherein the chemotherapeutic agent is selected from the group consisting of daunorubicin, daunorubicin HC1, and daunorubicin citrate.
85. The method of claim 57 , wherein the chemotherapeutic agent is methotrexate.