2. Academic Validation
  3. Discovery of a Potent and Selective Degrader for USP7

Discovery of a Potent and Selective Degrader for USP7

  • Angew Chem Int Ed Engl. 2022 Aug 15;61(33):e202204395. doi: 10.1002/anie.202204395.
Yuan Pei 1 2,  Jingfeng Fu 1 2,  Yunkai Shi 1 3,  Mengmeng Zhang 1,  Guanghao Luo 1 3 2,  Xiaomin Luo 1 4,  Ning Song 1 2,  Tian Mi 1 2,  Yaxi Yang 1 3 2,  Jia Li 1 3 2 5 4,  Yubo Zhou 1 3 2 5 4,  Bing Zhou 1 3 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, P.R. China.
PMID: 35691827 DOI: 10.1002/anie.202204395
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.

Keywords

Apoptotic Pathway; Mutant p53; PROTAC; USP7 Degrader; p53 Mutant Cancer Cells.

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