Wang Chengyan, Liu Hongchun, Song Zilan, Ji Yinchun, Xing Li, Peng Xia, Wang Xisheng, Ai Jing, Geng Meiyu, Zhang Ao
Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2544-2548. doi: 10.1016/j.bmcl.2017.03.088. Epub 2017 Mar 31.
Three series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and evaluated as RET kinase inhibitors. Compounds 23a and 23c were identified to show significant activity both in the biochemical and the BaF3/CCDC6-RET cell assays. Compound 23c was found to significantly inhibit RET phosphorylation and down-stream signaling in BaF3/CCDC6-RET cells, confirming its potent cellular RET-targeting profile. Different from other RET inhibitors with equal potency against KDR that associated with severe toxicity, 23c did not show significant KDR-inhibition even at the concentration of 1μM. These results demonstrated that 23c is a potent and selective RET inhibitor.
合成了三类吡唑并[3,4 - d]嘧啶衍生物，并将其作为RET激酶抑制剂进行评估。化合物23a和23c在生化和BaF3/CCDC6 - RET细胞试验中均显示出显著活性。发现化合物23c能显著抑制BaF3/CCDC6 - RET细胞中的RET磷酸化和下游信号传导，证实了其有效的细胞RET靶向特性。与其他对KDR具有同等效力且伴有严重毒性的RET抑制剂不同，即使在1μM的浓度下，23c也未显示出显著的KDR抑制作用。这些结果表明23c是一种有效的选择性RET抑制剂。
