Summary Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70. © 2013 Elsevier Ltd.
Rodina, A., Patel, P. D., Kang, Y., Patel, Y., Baaklini, I., Wong, M. J. H., … Chiosis, G. (2013). Identification of an allosteric pocket on human Hsp70 reveals a mode of inhibition of this therapeutically important protein. Chemistry and Biology, 20(12), 1469–1480. https://doi.org/10.1016/j.chembiol.2013.10.008