Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

The Hsp90 chaperone is a master regulator of the stability and activity of multiple oncoproteins such as Her2, Akt, Bcr-Abl, cKit, EGFR and mutant BRAF. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach. There are now 14 drug candidates that target Hsp90 undergoing clinical trials in multiple indications as single agents or combination therapy. These compounds represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design. Although the compounds fall into distinct classes with unique properties, each inhibitor binds in the N-terminal ATP pocket and accumulates in tumor tissue while being rapidly cleared from circulation and normal tissue. The most advanced candidates are now in Phase 2 clinical trials and defining the therapeutic window, dosing schedule, and indication are the primary challenges for these potential first-in-class inhibitors.