F1FO-ATP synthase is involved in the regulation of cellular ATP production and maintenance of the mitochondrial membrane potential. Cruentaren A, a macrolactone obtained from myxobacterium Byssovorax cruenta, is a highly selective inhibitor of F1FO-ATP synthase and is also a highly cytotoxic agent against select cancer cell lines. Hsp90, the most abundant heat shock protein, plays a vital role in the maturation of client proteins via the assistance of co-chaperones and partner proteins, such as F1FO ATP synthase. We have previously shown that cruentaren A selectively binds F1FO ATP synthase and disrupts the Hsp90-F1FO ATP synthase interaction resulting in client protein degradation without concomitant induction of the heat shock response (HSR). Previous SAR studies on Cruentaren A identified structural features leading to a more potent analog, which manifested an IC50 of 0.7 nM against the L-929 mouse fibroblast cell line. In this study, the structure of cruentaren A was simplified to identify the pharmacophore necessary for anticancer activity and inhibition of F1FO-ATP synthase.

Cruentaren A analogs and their biological activities

2019 Spring National Meeting

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