Development of Targeted Ansamycins as Noval Antiestrogens and Tyrosine Kinase Inhibitors
Final rept. 1 Sep 1997-31 Aug 2000
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
Pagination or Media Count:
The subject of this grant was the development of a novel class of anticancer agents that induces the degradation of specific proteins by causing them to bind in a stable complex with the chaperone molecule hsp90. This was to be accomplished by synthesizing hybrid drugs comprised of the hsp9o-binding drug geldanamycin covalently joined to a high affinity ligand for the protein to be degraded. The goal of this grant was to pilot this idea by making geldanamycin- estrogen hybrids to target the estrogen receptor. We succeeded in synthesizing several families of such hybrids, in determining characteristics of the linker moieties required for activity and in identifying compounds that selectively inhibit estrogen receptor, androgen receptor and various members of the P13 kinase family. Furthermore, we have shown that a compound that selectively degrades estrogen receptor has selective cytotoxic activity against ER-containing MCF-7 breast cancer cells and that a corresponding compound with activity against androgen receptor selectively inhibits the growth of prostate cancer cells.
- Medicine and Medical Research