Structure-based discovery of a specific SHP2 inhibitor with enhanced blood-brain barrier penetration from PubChem database

  • Bioorg Chem. 2022 Apr;121:105648. doi: 10.1016/j.bioorg.2022.105648.
Ying Ma  1 ,  Wei-Ya Li  1 ,  Ting Sun  2 ,  Ling Zhang  3 ,  Xin-Hua Lu  4 ,  Bing Yang  5 ,  Run-Ling Wang  6
Affiliations
  • 1. Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, People's Republic of China.
  • 2. Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China.
  • 3. School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China.
  • 4. New Drug Research & Development Center of North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering & Research Center, Hebei Industry Microbial Metabolic Engineering & Technology Research Center, Shijiazhuang, Hebei 050015, China.
  • 5. School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 6. Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, People's Republic of China. Electronic address: [email protected].
PMID: 35180489 DOI: 10.1016/j.bioorg.2022.105648
Abstract

The thiophene [2,3-d]pyrimidine structure-like small molecules were discovered from structure-based virtual screening of 1 billion compounds. Base on enzyme activity assay results, a SHP2-specific molecule inhibitor Comp#2 with IC50 of 1.174 μM, 85-fold more selective for SHP2 than the highly related SHP1 (IC50 > 100 μM). The compound can effectively inhibit SHP2-mediated cell signaling and Cancer cell proliferation, including cervix Cancer, human pancreatic Cancer, large cell lung Cancer, and mouse glioma cell. Moreover, the in vivo assay indicated that Comp#2 could inhibit cervix Cancer tumors growth in BABL/c mice. This work has shown the specific SHP2 Inhibitor can inhibit glioblastoma growth in vivo.

Keywords
Cancer cell proliferation; Glioblastoma growth; Inhibitor; SHP2; Synthesis; Virtual screening.
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