Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.The cyclopropane-1,1-dicarboxamide moiety might be critical for the potent dual inhibition of c-Met and VEGFR-2. Thieno[2,3-d]pyrimidine as the scaffold of potent kinase inhibitor was combined with the cyclopropane-1,1-dicarboxamide moiety to obtain potent c-Met and VEGFR-2 inhibitor.Download high-res image (107KB)Download full-size image