布加替尼作为新型EGFR突变体野生型保留抑制剂的优化
Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR Mutants.
作者信息
Li Shan, Zhang Tao, Zhu Su-Jie, Lei Chong, Lai Mengzhen, Peng Lijie, Tong Linjiang, Pang Zilu, Lu Xiaoyun, Ding Jian, Ren Xiaomei, Yun Cai-Hong, Xie Hua, Ding Ke
机构信息
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511436, China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
出版信息
ACS Med Chem Lett. 2022 Jan 7;13(2):196-202. doi: 10.1021/acsmedchemlett.1c00555. eCollection 2022 Feb 10.
A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. also demonstrated promising EGFR mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR with a close derivative was solved to provide insight on the inhibitor's binding mode. Moreover, compound was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.
设计并合成了一系列布吉他滨衍生物作为新型强效和选择性表皮生长因子受体（EGFR）抑制剂。其中一种最具效力和选择性的化合物分别以0.7 nM和3.6 nM的半数抑制浓度（IC值）强烈抑制EGFR和EGFR激酶，其效力比先导化合物高出54倍以上。该化合物还表现出有前景的EGFR突变体选择性，对野生型EGFR的效力低94倍。解析了EGFR与一种密切相关衍生物的共晶体结构，以深入了解该抑制剂的结合模式。此外，该化合物具有口服生物利用度，并表现出非常理想的药代动力学（PK）性质，使其成为进一步结构优化的有前景的先导化合物。
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