USP7-797

USP7-797 is a highly potent and selective oral small molecule inhibitor of ubiquitin-specific protease 7 (USP7), part of the deubiquitylating enzyme family that regulates the degradation of key proteins involved in cancer cell survival and DNA repair[1][4][2]. Its unique thienopyridine pharmacophore binds near the catalytic domain of USP7 and inhibits its enzymatic activity by sterically hindering ubiquitin binding[1]. By inhibiting USP7, USP7-797 disrupts the MDM2-p53 pathway, reducing MDM2 stability, increasing p53 stability and activity, and ultimately causing cell cycle arrest and apoptosis in tumor cells[2]. It has demonstrated potent antitumor effects in preclinical solid and hematologic malignancy models, including TP53 wild-type and mutant contexts[1][4]. USP7-797 is notable for sub-nanomolar potency and oral bioavailability, but has not entered human clinical trials as of the current knowledge[4]. Resistance mechanisms to USP7-797 have been observed in cell lines, most commonly due to a V517F mutation in USP7[1]. USP7 inhibition also increases tumor sensitivity to PARP, PLK1, and HDAC inhibitors in preclinical models[1][4].