CDC7 kinase inhibitors and uses thereof

• US 10,123,992 B2
• Filed: 10/10/2017
• Issued: 11/13/2018
• Est. Priority Date: 03/08/2010
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Frattini, Mark G., Djaballah, Hakim, Kelly, Thomas J.
• Primary Examiner(s): Krishnan, Ganapathy
• Application Number:
  US15/728,609
• Publication Number:
  US 20180125815A1
• Time in Patent Office: 399 Days
• Field of Search: 514 27, 514453, 514454
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 493/08 : Bridged systems
• CPC Class Codes: C07D 493/18 : Bridged systems
• CPC Class Codes: C09B 13/02 : of the naphthalene series, e.g. naphthazarin
• CPC Class Codes: C09B 61/00 : Dyes of natural origin prepared from natural sources , e.g. vegetable sources
• CPC Class Codes: C12Q 1/6886 : for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 : Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 : Polymorphic or mutational markers

Abstract

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.

Claims

1. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of Formula (II):

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.