Modulators of HEC1 activity and methods therefor
Compounds, compositions, and methods for modulation of Hec1/Nek2 interaction are provided. Especially preferred compounds disrupt Nek2/Hec1 binding and are therefore useful as chemotherapeutic agent for neoplastic diseases.
1. A method of treating a neoplastic disease, comprising:
administering to a mammal in need thereof a pharmaceutical composition comprising a compound having a structure according to Formula I
R 1 is alkyl, OR a , SR a , or —S(O) 2 R a ;
R a is alkyl, or aryl substituted with alkoxy;
R 2 and R 3 are independently alkyl;
R 4 is hydrogen;
R 5 is pyridyl optionally substituted with alkyl, fluoroalkyl, halogen, or alkoxy;
wherein the compound is present in the composition an amount effective to disrupt Hec1/Nek2 binding in the mammal when the composition is administered to the mannal; and
wherein the neoplastic disease is selected from the group consisting of breast cancer, prostate cancer, cervical cancer and leukemia.
2. The method of claim 1 wherein R 1 is SRa, ORa, or, —S(O)2Ra, and wherein Ra is aryl substituted with alkoxy.
3. The method of claim 1 , wherein the compound has a structure selected from the group consisting of
4. The method of claim 1 wherein the compound has the structure
5. The method of claim 1 wherein the compound has the structure
6. The method of claim 1 wherein the compound has the structure
7. The method of claim 1 wherein the compound has the structure
8. The method of claim 1 wherein the compound has the structure
9. The method of claim 1 wherein the compound has the structure
10. The method of claim 1 wherein the compound has the structure
11. The method of claim 1 wherein the compound has the structure
12. The method of claim 1 wherein the pharmaceutical composition is formulated for injection or oral administration.
13. The method of claim 1 wherein administration of the pharmaceutical composition also triggers Nek2 degradation.
14. The method of claim 1 wherein the compound has an antiproliferative effect on tumor cells with an IC50 of less than 1 microM.
15. The method of claim 1 , wherein the compound has the structure
16. The method of claim 1 , wherein the breast cancer is linked to MDA-MB468 or MDA-MB231, the prostate cancer is linked to PC-3, and the leukemia is linked to K562, KG-1, MV4-11 or RS4; 11.