Anticancer drugs that target tyrosine kinases have attracted considerable attention. Both c-Met and VEGFR-2 are important members of tyrosine kinase family.Molecules that simultaneously inhibit c-Met and VEGFR-2 may be superior to either c-Met-selective of VEGFR-2-selective inhibitor as they can interrupt multiple signaling pathways in tumor angiogenesis, proliferation, and metastasis. Recently several dual c-Met/VEGFR-2 inhibitors have been in clinical trials, including XL184, XL880, E7050, and MGCD265.

A series of potent dual c-Met and VEGFR-2 inhibitors bearing ananilinopyrimidine scaffold have been designed and synthesized. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for SAR exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent anti-proliferative effect against c-Met addictive cell lines with IC₅₀ values ranged from 0.33 μM to 1.7 μM.

This work has been published on ACS Medicinal Chemistry Letters (Zhengsheng Zhan, Jing Ai,Qiufeng Liu,Yinchun Ji,Tiantian Chen,Yechun Xu,*Meiyu Geng*, and Wenhu Duan*. Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity. ACS Med. Chem. Lett. 2014, 5 (6), 673-678).

Figure. Anilinopyrimidinesas dual c-Met/VEGFR-2 inhibitors (Image by SIMM)

(Source:Prof.Duan Wenhu's Group)