2. Academic Validation
  3. Novel PROTACs for degradation of SHP2 protein

Novel PROTACs for degradation of SHP2 protein

  • Bioorg Chem. 2021 May;110:104788. doi: 10.1016/j.bioorg.2021.104788.
Mengzhu Zheng 1,  Yang Liu 2,  Canrong Wu 1,  Kaiyin Yang 1,  Qiqi Wang 2,  Yirong Zhou 3,  Lixia Chen 4,  Hua Li 5
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
  • 4 Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 5 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 33706076 DOI: 10.1016/j.bioorg.2021.104788
Abstract

Protein tyrosine Phosphatase SHP2 is a member of PTPs family associated with Cancer such as leukemia, non-small cell lung Cancer, breast Cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell Apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.

Keywords

PROTAC; Protein degrader; SHP2.

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