METHODS OF TREATING A MEIOTIC KINESIN ASSOCIATED DISEASE

• US 20110190374A1
• Filed: 05/28/2009
• Published: 08/04/2011
• Est. Priority Date: 05/30/2008
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Pellman, David
• Granted Patent: US 8,629,118 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: G01N 2333/914 Hydrolases (3)
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/5026 on cell morphology
• CPC Class Codes: G01N 33/57496 involving intracellular compounds

Abstract

The invention provides methods of treating a meiotic kinase-associated disease, preferably the meiotic kinase HSET, by administering an inhibitor of the meiotic kinase. Preferably, the disease is associated with the presence of supernumerary centrosomes, such as cancer. Methods of inhibiting the growth of a tumor cell by contacting the cell with an inhibitor of a meiotic kinase, preferably HSET, are also provided. Screening methods for identifying inhibitors of the meiotic kinase HSET are also provided. Methods of selecting subjects for treatment with an inhibitor of a meiotic kinase, such as HSET, are also provided.

Claims

1. A method of treating a meiotic kinesin-associated disease or disorder, comprising administering to a subject in need of treatment thereof an agent which inhibits a meiotic kinesin such that treatment of the disease or disorder is achieved.

2. The method of claim 1, wherein the disease or disorder is an autosomal disease or disorder, a centrosomal disease or disorder, a cellular proliferative disease or disorder, or cancer.

6. The method of claim 1, wherein the meiotic kinesin is a kinesin-14 family member.

7. The method of claim 6, wherein the meiotic kinesin is HSET.

8. The method of claim 2, wherein the agent is a small molecule, an RNAi agent, the agent inhibits ATPas activity of the kinesin, or the agent inhibits microtubule binding activity of the kinesin.

12. The method of claim 8, wherein the agent is administered orally.

13. The method of claim 8, wherein the agent is administered parenterally.

3-5. -5. (canceled)

9-11. -11. (canceled)

14. A method of inhibiting growth of a tumor cell in which cellular proliferation is associated with a meiotic kinesin, comprising contacting the tumor cell with an agent which inhibits a meiotic kinesin such that growth of the tumor cell is inhibited.

15. The method of claim 14, wherein the tumor cell comprises supernumerary centrosomes.

16. The method of claim 14, wherein the meiotic kinesin is a kinesin-14 family member.

17. The method of claim 15, wherein the meiotic kinesin is HSET.

18. The method of claim 14, wherein the agent is a small molecule, an RNAi agent, the agent inhibits ATPas activity of the kinesin, or the agent inhibits microtubule binding activity of the kinesin.

22. The method of claim 14, wherein said contacting comprises direct injection of the agent into the tumor.

19-21. -21. (canceled)

23. A method of inhibiting proliferation of a cell in which cellular proliferation is associated with a meiotic kinesin, comprising contacting the cell with an agent which inhibits a meiotic kinesin such that inhibition of cell proliferation is achieved.

24. The method of claim 23, wherein the cell contains supernumerary centrosomes and the meiotic kinesin is a kinesin-14 family member.

26. The method of claim 24, wherein the meiotic kinesin is HSET.

27. The method of claim 23, wherein the agent is a small molecule, an RNAi agent, the agent inhibits ATPas activity of the kinesin, or the agent inhibits microtubule binding activity of the kinesin.

25. (canceled)

28-30. -30. (canceled)

31. A method for identifying a compound that inhibits activity of a meiotic kinesin HSET, the method comprising

providing an indicator composition comprising the meiotic kinesin HSET;

contacting the indicator composition with a test compound; and

determining activity of the meiotic kinesin HSET in the presence of the test compound, wherein reduction of activity of the meiotic kinesin HSET in the presence of the test compound, as compared to activity of the meiotic kinesin HSET in the absence of the test compound, identifies the test compound as a compound that inhibits the activity of a meiotic kinesin HSET.

32. The method of claim 31, wherein the indicator composition is contacted with each member of a library of test compounds and one or more test compounds within the library are selected that inhibit the activity of the meiotic kinesin HSET.

33. The method of claim 31, wherein the activity of the meiotic kinesin HSET is determined by measuring ATPase activity of the kinesin, measuring microtubule binding activity of the kinesin;

or measuring expression of HSET mRNA or protein.

34-36. -36. (canceled)

37. A method of selecting a subject with a tumor for treatment with an agent which inhibits a meiotic kinesin, the method comprising

(i) obtaining a tumor cell sample from the subject, and

(ii) determining centrosome number in the tumor cell sample, wherein the presence of supernumerary centrosomes in the tumor cell sample selects the subject for treatment with an agent which inhibits a meiotic kinesin.

38. The method of claim 37, wherein the meiotic kinesin is a kinesin-14 family member.

39. The method of claim 38, wherein the meiotic kinesin is HSET.

40. The method of claim 37, wherein at least 50% of tumor cells in the tumor cell sample contain supernumerary centrosomes.

42. The method of claim 37, wherein at least 90% of tumor cells in the tumor cell sample contain supernumerary centrosomes.

41. (canceled)