Details

Autor(en) / Beteiligte

• Zhan, Zhengsheng
• Ai, Jing
• Liu, Qiufeng
• Ji, Yinchun
• Chen, Tiantian
• Xu, Yechun
• Geng, Meiyu
• Duan, Wenhu

Titel

Discovery of Anilinopyrimidines as Dual Inhibitors of c‑Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Ist Teil von

• ACS medicinal chemistry letters, 2014-06, Vol.5 (6), p.673-678

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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 an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure–activity relationship (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 antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.