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Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR(T790M/C797S) Mutants

文献类型：期刊论文

作者Li, Shan1; Zhang, Tao2; Zhu, Su-Jie3; Lei, Chong4; Lai, Mengzhen2; Peng, Lijie1; Tong, Linjiang2; Pang, Zilu2; Lu, Xiaoyun1; Ding, Jian2
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2022-01-07
页码7
ISSN号1948-5875
关键词Epidermal Growth Factor Receptor (EGFR) Resistant Mutation C797S Antitumor
DOI10.1021/acsmedchemlett.1c00555
通讯作者Ren, Xiaomei(ren_xiaomei@jnu.edu.cn) ; Yun, Cai-Hong(yanch@bjmu.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Ding, Ke(dingke@jnu.edu.cn)
英文摘要A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR(T790M/C797S) inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFR(L858R/T790M/C797S) and EGFR (19Del/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 EGFR(T790M/C797S) mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR(T790M/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.
WOS关键词CELL LUNG-CANCER ; EGFR INHIBITORS ; C797S MUTATION ; RECEPTOR INHIBITORS ; OPEN-LABEL ; RESISTANCE ; DISCOVERY ; AZD9291 ; GEFITINIB ; EFFICACY
资助项目National Natural Science Foundation of China[21807045] ; National Natural Science Foundation of China[82173650] ; National Natural Science Foundation of China[81820108029] ; National Natural Science Foundation of China[81874284] ; National Natural Science Foundation of China[22037003] ; National Natural Science Foundation of China[22077050] ; National Natural Science Foundation of China[81903638] ; Guangdong Province[2021A1515011239] ; Guangdong Province[2018B030337001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-004] ; Chinese Academy of Sciences[XDA12020112]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000742736800001
源URL[http://119.78.100.183/handle/2S10ELR8/300718]  
专题新药研究国家重点实验室
通讯作者Ren, Xiaomei; Yun, Cai-Hong; Xie, Hua; Ding, Ke
作者单位1.Jinan Univ, Sch Pharm, Guangzhou City Key Lab Precis Chem Drug Dev, Minist Educ MOE China,Int Cooperat Lab Tradit Chi, Guangzhou 511436, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Qingdao Univ, Coll Med, Affiliated Hosp, Inst Translat Med, Qingdao 266021, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan Chem & Nat Prod, Shanghai 200032, Peoples R China
5.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biochem & Biophys,Inst Syst Biomed, Beijing 100191, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
推荐引用方式
GB/T 7714		 Li, Shan,Zhang, Tao,Zhu, Su-Jie,et al. Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR(T790M/C797S) Mutants[J]. ACS MEDICINAL CHEMISTRY LETTERS,2022:7.
APA Li, Shan.,Zhang, Tao.,Zhu, Su-Jie.,Lei, Chong.,Lai, Mengzhen.,...&Ding, Ke.(2022).Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR(T790M/C797S) Mutants.ACS MEDICINAL CHEMISTRY LETTERS,7.
MLA Li, Shan,et al."Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR(T790M/C797S) Mutants".ACS MEDICINAL CHEMISTRY LETTERS (2022):7.

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来源：上海药物研究所

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