Development of Small Molecule Hsp90 Inhibitors: Utilizing Both Forward and Reverse Chemical Genomics for Drug Identification

Len      Neckers

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and / or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2 / Neu (ErbB2), and HIF-1α. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have also shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trial. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Benzoquinone ansamycin binding to Hsp90 led to the identification of radicicol as an additional Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.

Keywords: molecular chaperones, heat shock protein 90, kinase inhibitors, benzoquinone ansamycins, radicicol, novobiocin, geldanamycin, molecularly targeted therapeutics