Discovery of Hsp70 inhibitors for allosteric dissociation of the Hsp70/BAG3 complex via structure-based de novo design.

Protein-protein interaction (PPI) with cochaperones could induce conformational changes of Hsp70. The Hsp70/BAG3 PPI shows tumor specificity and could be regarded as potential targets for cancer therapy. In this paper, a de novo structure-based design was carried out based on the analysis of conformational changes of Hsp70 in terms of the allosteric dissociation of BAG3. An effective small molecule, HAFI-11, was obtained and identified to bind at a novel allosteric site on the surface of Hsp70 through structure-activity relationship analysis and 2D 1H15N NMR studies. HAFI-11 binds to Hsp70 directly in cells and promotes the dissociation of the Hsp70/BAG3 PPI with stronger efficacy than MKT-077 did. Finally, HAFI-11 exhibits efficient antiproliferative activities in the μM range against MCF-7 cancer cells.