Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations

Abstract

Vascular endothelial growth factor receptor (VEGFR) is one of the well-known targets that control angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the new compounds were also designed to interact with residues in the solvent accessible region such as Asn923. Accordingly, the thienopyrimidine target compounds were synthesized and subjected to VEGFR-2 enzyme inhibition assay. Several target compounds (7d-f, 8b-c, 8e-g and 15c) exhibited potent inhibitory activities against VEGFR-2 with IC₅₀ values in low nanomolar range. Compounds 8b and 8e revealed exceptionally potent inhibitory activity with IC₅₀ of 5 and 3.9 nM, respectively. The molecular docking analysis and molecular dynamics simulation were also performed to further investigate these findings.

Keywords: Antiangiogenic activity; Docking; Kinase inhibitors; Thienopyrimidine; VEGFR-2 inhibitors.