Tamoxifen enhances the Hsp90 molecular chaperone ATPase activity

Abstract

Background: Hsp90 is an essential molecular chaperone that is also a novel anti-cancer drug target. There is growing interest in developing new drugs that modulate Hsp90 activity. Methodology/Principal Findings: Using a virtual screening approach, 4-hydroxytamoxifen, the active metabolite of the anti-estrogen drug tamoxifen, was identified as a putative Hsp90 ligand. Surprisingly, while all drugs targeting Hsp90 inhibit the chaperone ATPase activity, it was found experimentally that 4-hydroxytamoxifen and tamoxifen enhance rather than inhibit Hsp90 ATPase. Conclusions/Significance: Hence, tamoxifen and its metabolite are the first members of a new pharmacological class of Hsp90 activators. © 2010 Zhao et al.