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  2. Design, synthesis, anticancer activity evaluation and molecular dynamics study of pyrazine N-oxide-based SHP2 allosteric inhibitors

Design, synthesis, anticancer activity evaluation and molecular dynamics study of pyrazine N-oxide-based SHP2 allosteric inhibitors

  • Eur J Med Chem. 2025 Apr 30:293:117687. doi: 10.1016/j.ejmech.2025.117687.
Xin Wang 1 Xiaoyu Shao 1 Meijing Wang 2 Yan Li 1 Tongtong Geng 1 Yashuai Wang 1 Xuyang Ding 1 Yichao He 1 Hongwei Jin 1 Yang Sun 2 Zhongjun Li 3 Xiangbao Meng 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: zjli@bjmu.edu.cn.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: xbmeng@bjmu.edu.cn.
Abstract

Src homology-2-containing protein tyrosine Phosphatase 2 (SHP2), the first oncoprotein identified in the protein Phosphatase family, has emerged as a promising Anticancer target in recent years. Here, we report the discovery of a novel series of pyrazine N-oxide derivatives as potent SHP2 allosteric inhibitors and the identification of compound C5 as a highly potent and selective SHP2 allosteric inhibitor (SHP2WT IC50 = 0.023 μM, SHP2E76K IC50 = 0.119 μM). At the cellular level, C5 exerted significant antiproliferative effect on KYSE-520 and MV-411 cells (KYSE-520 IC50 = 6.97 μM, MV-411 IC50 = 0.67 μM) and induced Apoptosis of MV-411 cells by downregulating the SHP2-mediated ERK cell signaling. Molecular dynamics simulations revealed that C5 could form stable hydrogen bond interactions, cation-π interactions and water bridges with key residues Glu110, Arg111, Phe113, Gly115 and Thr253, thereby effectively binding to the tunnel allosteric site of SHP2. Notably, the pyrazine N-oxide scaffold could additionally form a strong and stable hydrogen bond with Arg111. Collectively, this work uncovers a novel and potent scaffold as well as presents compound C5 as a promising lead for the development of new chemotypes of SHP2 allosteric inhibitors.

Keywords

Allosteric inhibitor; Anticancer activity; Drug design; Molecular dynamics simulation; SHP2.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172911
    SHP2 Inhibitor