Discovery of novel flavonoid derivatives targeting VEGFR2 and tubulin with potent anticancer efficacy.

The clinical efficacy of VEGFR inhibitors and tubulin inhibitors as monotherapies is restricted by adverse reactions and resistance. We reported a classic pharmacophore hybridization strategy to develop dual VEGFR2/tubulin inhibitors that simultaneously inhibited tumor angiogenesis and tubulin assembly. A series of novel flavonoid derivatives containing N, N'-diethylurea group and trimethoxyphenyl were designed and synthesized. Among them, compound 6r demonstrated excellent antitumor activity in vitro and in vivo. Mechanistic studies revealed that 6r exerted antitumor activity by inhibiting VEGFR2 and tubulin in the micromolar range. Further studies showed that 6r inhibited angiogenesis in the CAM model. Additionally, 6r also demonstrated moderate PK profiles with broad tissue distribution characteristics and good safety. Notably, 6r inhibited tumor growth in the HGC-27 xenograft model. All the reported results suggested that 6r may be a potent anticancer candidate and merited further investigation.