HSP70 is a key molecular chaperone that is overexpressed in many cancers. It has proved difficult to develop clinical inhibitors of HSP70 by traditional drug discovery methods due to the flexible and hydrophilic nature of the ATP binding site and its high affinity for natural nucleotides. The aim of this work was to identify allosteric inhibitors of HSP70 using fragment based drug discovery. A fragment screen, designed to find allosteric inhibitors of HSP70, was carried out using Surface Plasmon Resonance to detect hits. The use of both wild type Tr-HSC70 and an ATP binding site mutant S275W allowed the identification of fragment hits outside of the ATP binding site. The x-ray crystal structure of a fragment hit was solved and found to bind to a previously undescribed allosteric site of HSP70, adjacent to the ATP binding site. Characterization of the binding site and analogues of the fragment hit was carried out using a variety of orthogonal techniques including SPR, CPMG and WaterLOGSY. This new ligand binding site of HSP70 may provide additional opportunities for future drug design.

Discovery and characterization of a novel allosteric binding site of HSP70 by fragment based screening

2019 Spring National Meeting

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