Discovery and Characterization of Highly Potent and Selective Allosteric USP7 Inhibitors

Gavory G, et al., 14(2):118-125, Nat Chem Biol, 2018

Ubiquitin-specific protease 7 (USP7) is involved in multiple oncogenic pathways. Reported herein is the discovery and detailed characterization of highly potent and selective small molecule inhibitors of USP7. Authors demonstrate that the lead compounds identified in this study inhibit USP7 in a noncovalent and reversible manner. Furthermore, the first reports of high-resolution X-ray crystal structures of USP7 in complex with small-molecule inhibitors were also revealed. Small molecule inhibitors binding to USP7 were studied by Surface Plasmon Resonance (SPR) technology using a Pall ForteBio Pioneer system. The USP7 catalytic domain (residues 207-560) was expressed in E. coli cells. The purified proteins were immobilized onto the surface of the COOH5 sensor chip by using standard amine coupling chemistry. Subsequently, small molecule samples were diluted in running buffer and injected. SPR data obtained were analyzed using Qdat data analysis software. KD values were determined. Taken together, the results of this study demonstrate amenability and druggability of USP7 inhibitors and hence provides important insights for future target validation studies.

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