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Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR(del19/T790M/C797S) and EGFR(L858R/T790M/C797S))

文献类型：期刊论文

作者Fang, Haotian3,4; Wu, Yingming2; Xiao, Qitao1,2; He, Dongbo2; Zhou, Tongrui2; Liu, Wenzhong2; Yang, Chun-Hao3,4; Xie, Yuli2
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2022-09-15
卷号72页码:11
关键词Non-small cell lung cancer EGFR Triple mutations C797S EGFR-TKIs
ISSN号0960-894X
DOI10.1016/j.bmcl.2022.128729
通讯作者Xie, Yuli(ylxie@wigenbio.com)
英文摘要Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFR(del19/T790M/C797S) and EGFR(L858R/T790M/C797S) are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib. After extensive SAR studies, compound 23, the most promising candidate, exhibited strong biochemical potencies against EGFR(del19/T790M/C797S), EGF(L858R/T790M/C797S) and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3EGFR (el19/T790M/C797S) and PC-9EGFR (del19/T790M/C797S). Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.
WOS关键词OSIMERTINIB ; RESISTANCE ; MECHANISMS ; THERAPY
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000814727000003
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301812]  
专题中国科学院上海药物研究所
通讯作者Xie, Yuli
作者单位1.Shanghai Blueray Biopharm Co Ltd, Bldg 3,576,Libing Rd, Shanghai 201210, Peoples R China
2.Wigen Biomed Technol Shanghai Co Ltd, 11Lane 67,Libing Rd, Shanghai 201210, Peoples R China
3.Univ Chinese Acad Sci, 19(A) Yuquan Rd,Shijingshan Dist, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Fang, Haotian,Wu, Yingming,Xiao, Qitao,et al. Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR(del19/T790M/C797S) and EGFR(L858R/T790M/C797S))[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2022,72:11.
APA Fang, Haotian.,Wu, Yingming.,Xiao, Qitao.,He, Dongbo.,Zhou, Tongrui.,...&Xie, Yuli.(2022).Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR(del19/T790M/C797S) and EGFR(L858R/T790M/C797S)).BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,72,11.
MLA Fang, Haotian,et al."Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR(del19/T790M/C797S) and EGFR(L858R/T790M/C797S))".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 72(2022):11.

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来源：上海药物研究所

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