Cruentaren A Binds F(1)F(0) ATP Synthase To Modulate the Hsp90 Protein Folding Machinery

[Image: see text] The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically, small molecules have been designed to inhibit ATPase activity at the Hsp90 N-terminus; however, these molecules also induce the pro-survival heat shock response (HSR). Therefore, inhibitors that exhibit alternative mechanisms of action that do not elicit the HSR are actively sought. Small molecules that disrupt Hsp90-co-chaperone interactions can destabilize the Hsp90 complex without induction of the HSR, which leads to inhibition of cell proliferation. In this article, selective inhibition of F(1)F(0) ATP synthase by cruentaren A was shown to disrupt the Hsp90-F(1)F(0) ATP synthase interaction and result in client protein degradation without induction of the HSR.