Sun Qi-Zheng, Xu Yong, Liu Jing-Jing, Zhang Chun-Hui, Wang Ze-Rong, Zheng Ren-Lin, Wang Wen-Jing, Li Lin-Li, Yang Sheng-Yong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China.
Mol Divers. 2014 May;18(2):403-9. doi: 10.1007/s11030-014-9508-8. Epub 2014 Feb 11.
Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an IC(50) value of 7 nM.
在此，我们描述了一种已知的表皮生长因子受体（EGFR）抑制剂（化合物1）的结构优化，该抑制剂对RET显示出较弱的脱靶活性。我们合成了化合物1的26种类似物。通过构效关系（SAR）分析发现了几种对依赖RET的甲状腺癌细胞系TT具有相当效力的化合物。然后在细胞试验中测定了最具活性的化合物（2u）的激酶抑制效力。结果表明，2u是一种有效的RET抑制剂，其半数抑制浓度（IC50）值为7 nM。
