Tamoxifen enhances the Hsp90 molecular chaperone ATPase activity

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.