Discovery of Novel Potent VEGFR‑2 Inhibitors Exerting Significant Antiproliferative Activity against Cancer Cell Lines

Computational
and experimental studies were applied to the discovery
of a series of novel vascular endothelial growth factor receptor 2
(VEGFR-2) inhibitors. Eight compounds exhibited nanomolar IC50 values against VEGFR-2, and compounds 6, 19, 22, and 23 showed potent antiproliferative
effects against several cell lines. Particularly, compound 23 behaved better than FDA approved drugs, sorafenib and sunitinib,
in antiproliferative activity against cell lines related to all nine
tumor types tested (GI50 values), and it was better or
comparable in safety (LC50 values). Compound 23 even demonstrated a high potency on one of the drug-resistant cell
lines (NCI/ADR-RES) responsible for ovarian cancer and cell lines
contributing to prostate cancer, regarded as one of the VEGF/VEGFR
pathway drug-resistant tumors. This compound is likely a promising
candidate for the treatment of leukemia, non-small cell lung cancer
(NSCLC), colon cancer, ovarian cancer, and breast cancer with a suitable
balance of both efficacy and safety.