Search

• New c-Met and VEGFR-2 dual inhibitors were designed and synthesized. • Enzymatic activities against c-Met and VEGFR-2 were evaluated. • Cellular inhibitory activities against MHCC97H, HUVEC, HEK293 and LO2 cell lines were conducted. • Anti-tumor activity was observed in MHCC97H cells xenograft model in vivo assay. Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3- f ]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC 50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro , compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy. [ABSTRACT FROM AUTHOR]