2. Academic Validation
  3. Design, synthesis and biological activity of dimeric pyrazolo[3,4-d]pyrimidin-4-one derivatives as selective SHP2 orthosteric inhibitors

Design, synthesis and biological activity of dimeric pyrazolo[3,4-d]pyrimidin-4-one derivatives as selective SHP2 orthosteric inhibitors

  • Bioorg Chem. 2026 Apr:171:109573. doi: 10.1016/j.bioorg.2026.109573.
Yashuai Wang 1,  Xiaoyu Shao 1,  Meijing Wang 2,  Zhongjun Li 1,  Yang Sun 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 210046, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210046, China. Electronic address: sunyangnju@163.com.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.. Electronic address: xbmeng@bjmu.edu.cn.
PMID: 41628498 DOI: 10.1016/j.bioorg.2026.109573
Abstract

SHP2 is a key oncoprotein and a promising target in various types of blood cancers and solid tumors. Here, we report the discovery of a novel series of dimeric pyrazolo[3,4-d]pyrimidin-4-one derivatives as potent SHP2 inhibitors. Among them, compound A4 exhibited potent inhibitory activity against both SHP2WT and SHP2E76K, and it demonstrated dose-dependent activity against the SHP2 protein tyrosine Phosphatase (PTP) domain. At the cellular level, A4 significantly suppressed the proliferation of MV-4-11, KYSE520, HCT116, MDA-MB-231 and HepG2 cell lines. Further mechanistic studies revealed that A4 downregulated SHP2-mediated phosphorylation of Akt and ERK, and induced Apoptosis in MV-4-11 cells. Molecular docking revealed a comprehensive network of interactions between A4 and the SHP2-PTP domain, providing a structural basis for its potent inhibitory activity. Collectively, this work identifies compound A4 as a promising selective SHP2 orthosteric inhibitor with a distinct chemical scaffold.

Keywords

Anticancer activity; Drug design; Pyrazolopyrimidinone; SHP2; SHP2(E76K).

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