| Abstract
| - Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due toits role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability.Here we present a combined structure- and dynamics-based computational design strategy, taking the flexibilityof the receptor and of a lead peptidic antagonist into account explicitely, to identify the nonpeptidic smallmolecule 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) as a structurally novel inhibitorof Hsp90. The compound is selected to bind the Hsp90 N-terminal domain, mimicking the chemical andconformational properties of the recently described peptidic antagonist of the survivin−Hsp90 complex,shepherdin [Plescia et al. Cancer Cell2005, 7, 457−468]. Experimental tests show that AICAR binds theHsp90 N-domain, destabilizes multiple Hsp90 client proteins in vivo, including survivin, and exhibitsantiproliferative and proapoptotic activity in multiple tumor cell lines, while not affecting proliferation ofnormal human fibroblasts. We propose that AICAR represents a viable lead for further development ofanticancer drugs with wide therapeutic opportunities.
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