Design and Discovery of Quinazoline- and Thiourea-Containing Sorafenib Analogs as EGFR and VEGFR-2 Dual TK Inhibitors

Abstract

Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (<b>10a</b>-<b>v</b>) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds <b>10b</b> and <b>10q</b> which exhibited the most potent inhibitory activities against EGFR (IC₅₀ = 0.02 µM and 0.01 µM, respectively), VEGFR-2 (IC₅₀ = 0.05 µM and 0.08 µM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.