Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases
View Patent ↗Bifunctional molecules comprising two hsp-binding moieties which bind to hsp90 in the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.
1. A chemical compound comprising first and second hsp-binding moieties which bind to the pocket of hsp90 with which ansamycin antibiotics bind, said binding moieties being connected to one another by a linker, wherein the first and second hsp-binding moieties are each an ansamycin antibiotic and retain the ability in the chemical compound to bind to the pocket of hsp90.
2. The chemical compound of claim 1 wherein at least one of the hsp-binding moieties is geldanamycin, and the linker is connected to the 17-carbon of the geldanamycin.
3. The chemical compound of claim 2 wherein the linker has a length of 4 to 7 carbon atoms.
4. The chemical compound of claim 1 wherein the first and second hsp-binding moieties are geldanamycin and the linker is connected to the 17-carbons of the geldanamycins.
5. The chemical compound of claim 4 wherein the linker has a length of 4 to 7 carbon atoms.
6. The chemical compound of claim 5 wherein the linker has a length of 4 carbon atoms.
7. A method for destruction of cells expressing a HER-family tyrosine kinase, comprising administering to the cells a chemical compound comprising first and second hsp-binding moieties which bind to the pocket of hsp90 with which ansamycin antibiotics bind, said binding moieties being connected to one another by a linker, wherein the first and second hsp-binding moieties are each an ansamycin antibiotic and retain the ability in the chemical compound to bind to the pocket of hsp90.
8. A method for treating cancer in a patient suffering from cancer, comprising administering to the patient a therapeutic composition comprising a chemical compound comprising first and second hsp-binding moieties which bind to the pocket of hsp90 with which ansamycin antibiotics bind, said binding moieties being connected to one another by a linker, wherein the first and second hsp-binding moieties are each an ansamycin antibiotic and retain the ability in the chemical compound to bind to the pocket of hsp90.
9. The method of claim 8 wherein the cancer is an HER-positive cancer.
10. The method according to claim 8 wherein at least one of the hsp-binding moieties is geldanamycin, and the linker is connected to the 17-carbon of the geldanamycin.
11. The method according to claim 10 wherein the linker has a length of 4 to 7 carbon atoms.
12. The method according to claim 11 wherein the linker has a length of 4 carbon atoms.
13. The method according to claim 8 wherein the first and second binding moieties are geldanamycin, and the linker is connected to the 17-carbons of the geldanamycins.
14. The method according to claim 13 wherein the linker has a length of 4 to 7 carbon atoms.
15. The method according to claim 14 wherein he linker has a length of 4 carbon atoms.
16. The method according to claim 9 wherein at least one of the hsp-binding moieties is geldanamycin, and the linker connected to the 17-carbon of the geldanamycin.
17. The method according to claim 16 wherein the linker has a length of 4 to 7 carbon atoms.
18. The method according to claim 17 wherein the linker has a length of 4 carbon atoms.
19. The method according to claim 7 wherein the first and second binding moieties are geldanamycin, and the linker is connected to the 17-carbons of the geldanamycins.
20. The method according to claim 19 wherein the linker has a length of 4 to 7 carbon atoms.
21. The method according to claim 20 wherein the linker has a length of 4 carbon atoms.
22. The method according to claim 7 wherein at least one of the hsp-binding moieties is geldanamycin, and the linker is connected to the 17-carbon of the geldanamycin.
23. The method according to claim 22 wherein the linker has a length of 4 to 7 carbon atoms.
24. The method according to claim 23 wherein the linker has a length of 4 carbon atoms.
25. The method of claim 8 wherein the cancer is one in which the cancer cells overexpress a HER-family kinase.
26. The method of claim 8 wherein the cancer is breast cancer.
27. The method of claim 8 wherein the cancer is ovarian cancer.
28. The method of claim 8 wherein the cancer is pancreatic cancer.
29. The method of claim 8 wherein the cancer is gastric cancer.