Hsp90 is a molecular chaperone of pivotal importance\udfor multiple cell pathways. ATP-regulated internal dynamics\udare critical for its function and current pharmacological\udapproaches block the chaperone with ATP-competitive\udinhibitors. Herein, a general approach to perturb Hsp90\udthrough design of new allosteric ligands aimed at modulating\udits functional dynamics is proposed. Based on the characterization\udof a first set of 2-phenylbenzofurans showing\udstimulatory effects on Hsp90 ATPase and conformational dynamics,\udnew ligands were developed that activate Hsp90 by\udtargeting an allosteric site, located 65 æ from the active site.\udSpecifically, analysis of protein responses to first-generation\udactivators was exploited to guide the design of novel derivatives\udwith improved ability to stimulate ATP hydrolysis. The\udmolecules’ effects on Hsp90 enzymatic, conformational, cochaperone\udand client-binding properties were characterized\udthrough biochemical, biophysical and cellular approaches.\udThese designed probes act as allosteric activators of the\udchaperone and affect the viability of cancer cell lines for\udwhich proper functioning of Hsp90 is necessary.
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