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

We report a specific SHP2 inhibitor-Comp#2, which inhibits SHP2-mediated cell signaling and cancer cell proliferation and inhibits cervix cancer tumors glioblastoma growth in vivo . • This article first reported Comp#2 as a specific inhibitor of SHP2 (IC50 1.174 μM). • The Comp#2 had enhanced blood–brain barrier penetration than SHP099. • The Comp#2 inhibited SHP2-mediated cell signal transduction and cancer cell proliferation, and inhibited the growth of cervix cancer tumors and glioblastoma growth in vivo. 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 IC 50 of 1.174 μM, 85-fold more selective for SHP2 than the highly related SHP1 (IC 50 > 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 .