CDC7 kinase inhibitors and uses thereof
The invention provides compounds, methods, pharmaceutical compositions, and kits for the treatment of proliferative disorders such as cancer. In one aspect, the methods comprise compounds that inhibit the activity of protein kinases, such as cell division cycle (Cdc) kinase. In another aspect, the methods comprise compounds that inhibit Cdc7 and/or Dbf4 activity. In another aspect, the methods comprise compounds that exhibit anti-proliferative properties useful in treating diseases such as cancer. Compounds useful for any of the methods include compounds of the Formula (A) or (B): or pharmaceutically acceptable salts thereof. Exemplary compounds of Formula (A) or (B) include granaticin A, granaticin B, dihydrogranaticin A, dihydrogranaticin B, medermycin, and actinorhodin.
1. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein the cancer is selected from the group consisting of bone cancer, brain cancer, endocrine gland cancer, endometrial cancer, head and neck cancer, cancer of the larynx and hypopharynx, muscle cancer, testicular cancer, urethral cancer, bladder cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, small-cell lung cancer, sarcoma, esophageal cancer, gall bladder cancer, stomach cancer, myelodysplastic syndrome, renal cell carcinoma, skin cancer, lymphoma, tumors of the central and peripheral nervous system, and osteosarcoma.
2. The method of claim 1 , wherein the cancer is lymphoma.
3. The method of claim 1 , wherein the cancer is myelodysplastic syndrome.
4. The method of claim 1 , wherein the cancer is colon cancer.
5. The method of claim 1 , wherein the cancer is rectal cancer.
6. The method of claim 1 , wherein the cancer is stomach cancer.
7. The method of claim 1 , wherein the cancer is gall bladder cancer.
8. The method of claim 1 , wherein the cancer is liver cancer.
9. The method of claim 1 , wherein the cancer is small-cell lung cancer.
10. The method of claim 1 , wherein the cancer is kidney cancer or renal cell carcinoma.
11. The method of claim 1 , wherein the cancer is renal cell carcinoma.
12. The method of claim 1 , wherein the cancer is endometrial cancer.
13. The method of claim 1 , wherein the cancer is testicular cancer.
14. The method of claim 1 , wherein the cancer is bladder cancer.
15. The method of claim 1 , wherein the cancer is urethral cancer.
16. The method of claim 1 , wherein the cancer is an astrocytoma, neuroblastoma, or glioma.
17. The method of claim 1 , wherein the cancer is head and neck cancer.
18. The method of claim 1 , wherein the cancer is esophageal cancer.
19. The method of claim 1 , wherein the cancer is cancer of the endocrine glands.
20. The method of claim 1 , wherein the cancer is bone cancer.
21. The method of claim 1 , wherein the cancer is osteosarcoma.
22. The method of claim 1 , wherein the cancer is muscle cancer.
23. The method of claim 1 , wherein the subject is a human.
24. The method of claim 1 , wherein the cancer comprises a genetic mutation.
25. The method of claim 24 , wherein the genetic mutation comprises a RAS mutation, an EGFR mutation, a KRAS mutation, a p53 mutation, a BRAF mutation, a EVI1 mutation, a Flt-3 mutation, WT-1 mutation, a cyclin D mutation, a PTEN mutation, an ABL kinase mutation, or a chromosomal abnormality.
26. The method of claim 1 , wherein the cancer is a multi-drug resistant (MDR) cancer.
27. The method of claim 1 , wherein the cancer is a relapsed or refractory cancer.
28. The method of claim 1 further comprising administering an additional therapeutic agent.
29. The method of claim 1 further comprising administering radiation.
30. The method of claim 2 , wherein the cancer is B-cell lymphoma.
31. The method of claim 2 , wherein the cancer is T-cell lymphoma.
32. The method of claim 1 , wherein the cancer is cancer of the hypopharynx.