Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable antiangiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.

Automated summary

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared as potential inhibitors of VEGFR-2 using 3D modeling. Compound I10 showed more potent inhibitory activity (IC50 = 0.11 nM) against VEGFR-2 compared to most listed drugs, and it was confirmed as a selective VEGFR-2 inhibitor. 3D modeling predicted a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable antiangiogenesis and anti-proliferation effects in HUVEC at low nanomolar concentrations, and PK studies showed adequate oral bioavailability. In vivo subcutaneous tumor model demonstrated potent efficacy of I10 in inhibiting tumor growth and angiogenesis, indicating its potential as a drug candidate for cancer treatment.