Geng Kaijun, Xia Zongjun, Ji Yinchun, Zhang Ruisi Ruthy, Sun Deqiao, Ai Jing, Song Zilan, Geng Meiyu, Zhang Ao
CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, 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; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
Eur J Med Chem. 2018 Jan 20;144:386-397. doi: 10.1016/j.ejmech.2017.12.060. Epub 2017 Dec 20.
To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diarylaminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors.
为解决由ALK激酶突变引起的耐药性问题，尤其是针对第二代ALK抑制剂最具难治性且占主导地位的突变G1202R，通过引入间苯二酚部分（A环）来与G1202R所在的ALK激酶结构域相互作用，设计了一系列新的二芳基氨基嘧啶类似物。化合物12d表现出最强的活性，对ALK野生型、守门人突变体L1196M和G1202R突变体的IC值分别为1.7、3.5和1.8 nM。更重要的是，化合物12d对特异性表达ALK野生型、守门人L1196M和最具挑战性的突变体G1202R的BaF3细胞增殖具有优异的抑制作用，IC值均小于1.5 nM。总体而言，化合物12d作为一种新的更有效的第三代ALK抑制剂，有望进一步研究以克服第一代和第二代抑制剂的耐药性。
