Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFRT790M/C797S Mutants.
Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFRT790M/C797S Mutants.
复制标题
DOI：
10.1021/acsmedchemlett.1c00555
复制
发表时间：
2022-01
影响因子：
4.2
通讯作者：
Shanshan Li;Zhang Tao;Su-Jie Zhu;Chong Lei;Mengzhen Lai;Lijie Peng;Lin-jiang Tong;Zilu Pang;Xiaoyun Lu;Jian Ding;Xiaomei Ren;C. Yun;Hua Xie;Ke Ding
中科院分区：
文献类型：
--
作者：
Shanshan Li;Zhang Tao;Su-Jie Zhu;Chong Lei;Mengzhen Lai;Lijie Peng;Lin-jiang Tong;Zilu Pang;Xiaoyun Lu;Jian Ding;Xiaomei Ren;C. Yun;Hua Xie;Ke Ding
设计并合成了一系列Brigatinib衍生物，作为新的强效和选择性EGFRT 790 M/C797 S抑制剂。最有效和选择性的化合物之一18 k强烈抑制EGFRL 858 R/T790 M/C797 S和EGFR 19 Del/T790 M/C797 S激酶，IC 50值分别为0.7和3.6 nM，其效力是先导化合物的54倍以上。18 k也表现出有希望的EGFRT 790 M/C797 S突变体选择性，并且对野生型EGFR的效力低94倍。解析EGFRT 790 M/C797 S与接近衍生物18 f的共晶结构，以提供对抑制剂结合模式的了解。此外，化合物18 k是口服生物可利用的，并表现出非常理想的PK性质，使其成为进一步结构优化的有前途的先导化合物。
A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFRT790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFRL858R/T790M/C797S and EGFR19Del/T790M/C797S kinases with IC50 values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFRT790M/C797S mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFRT790M/C797S with a close derivative 18f was solved to provide insight on the inhibitor's binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.