Discovery of a Potent and Selective Degrader for USP7
Yuan Pei1,2, Jingfeng Fu1,2, Yunkai Shi1,3
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
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.
Insights
Researchers developed U7D-1, the first Proteolysis Targeting Chimera (PROTAC) that degrades USP7. This novel approach shows promise for treating p53 mutant cancers, unlike USP7 inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- p53 mutations are prevalent in human cancers, posing therapeutic challenges.
- USP7 stabilizes MDM2, which degrades the tumor suppressor p53.
- Targeting USP7 is a potential strategy for p53 mutant cancer therapy.
Purpose of the Study:
- To design and characterize a novel Proteolysis Targeting Chimera (PROTAC) targeting USP7.
- To evaluate the efficacy of USP7 degradation in p53 mutant cancer cells.
Main Methods:
- Design and synthesis of U7D-1, a selective USP7-degrading PROTAC.
- In vitro characterization of U7D-1's USP7 degradation activity.
- Assessment of U7D-1's effect on p53 mutant cancer cell growth.
Main Results:
- U7D-1 demonstrated selective and effective degradation of USP7.
- U7D-1 potently inhibited cell growth in p53 mutant cancer cells.
- USP7 inhibitors showed no activity against these cancer cells.
Conclusions:
- PROTACs represent a practical chemical tool for studying USP7 function.
- USP7-degrading PROTACs offer a promising therapeutic strategy for p53 mutant cancers.
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