Discovery of a Potent and Selective Degrader for USP7

Abstract

The tumor suppressor p53 is the most frequently mutated gene in human cancer and more than half of cancers contain p53 mutations. The development of novel and effective therapeutic strategies for p53 mutant cancer therapy is a big challenge and highly desirable. Ubiquitin-specific protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme and proposed to stabilize the oncogenic E3 ubiquitin ligase MDM2 that promotes the proteosomal degradation of p53. Herein, we report the design and characterization of U7D-1 as the first selective USP7-degrading Proteolysis Targeting Chimera (PROTAC). U7D-1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USP7 inhibitor showing no activity. These data clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP7 protein functions and a promising method for potential p53 mutant cancer therapy.

USP7 Inhibitors in Cancer Immunotherapy: Current Status and Perspective

“…Therefore, the selectivity of USP7 inhibitors should be considered early in their development. A recently reported series of molecules with an excellent potency and selectivity profile [ 92 , 93 , 94 , 95 ], as well as anti-USP7 proteolysis targeting chimera (PROTAC) compounds U7D-1 [ 96 ] and CST967 [ 97 ] represent an effort to expand a range of novel approaches for USP7 inhibition.…”

Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation

“…Recently, Zhou et al designed and synthesized the first-generation small-molecule degrader U7D-1 (26, Figure 7B) that can efficiently and selectively degrade USP7 (DC 50 = 33 nM). 91 degradation of USP7 by regulating the non-enzymatic functional regions (apoptosis and E2F pathway) of USP7 to exert antitumor activity against p53 mutant cancer cells.…”

“…Recently, Zhou et al designed and synthesized the first-generation small-molecule degrader U7D-1 (26, Figure 7B) that can efficiently and selectively degrade USP7 (DC 50 = 33 nM). 91…”

“…Ubiquitin-specific protease 7 (USP7) plays a key role in regulating p53 content by de-ubiquitinating and stabilizing MDM2. Recently, Zhou et al designed and synthesized the first-generation small-molecule degrader U7D-1 ( 26 , Figure B) that can efficiently and selectively degrade USP7 (DC 50 = 33 nM) . Compound 26 exhibited inhibitory activity against the growth of p53 wild-type cancer cells comparable to or stronger than that of USP7 inhibitors 27 .…”