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. Epub 2022 Jan 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Cell Proliferation
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mice
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11*
  • Uterine Cervical Neoplasms*

Substances

  • Enzyme Inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11