Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations
文献类型：期刊论文
| 作者 | Chen, Hao1,2; Lai, Mengzhen3,4; Zhang, Tao3; Chen, Yuqing1,2; Tong, Linjiang3; Zhu, Sujie5; Zhou, Yang1,2; Ren, Xiaomei6; Ding, Jian3,7 ; Xie, Hua3,7,8
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-05-12 |
| 卷号 | 65期号:9页码:6840-6858 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00168 |
| 文献子类 | Article |
| 英文摘要 | tertiary C797S mutation of epidermal growthfactor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need.Several classes of adenosine 5 '-triphosphate-competitive orallosteric EGFRT790M/C797Sinhibitors and degraders have beendeveloped, but none of them have received approval from theregulatory agencies. Herein, we report the structure-based design ofconformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenyl-aminopyrimidines as new EGFRT790M/C797Sinhibitors by using amacrocyclization strategy. Representative compound18jpotentlyinhibited EGFR19del/T790M/C797Sand EGFRL858R/T790M/C797Smutantswith IC50values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797Sand Ba/F3-EGFR19del/T790M/C797Scells withIC50values of 0.036 and 0.052 mu M, respectively, which is 10-20-fold more potent than brigatinib.18jalso potently inhibited theEGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50value of 0.644 mu M but was less potent for parentalBa/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance inNSCLC patients. |
| WOS关键词 | EGFR KINASE INHIBITORS ; BRIGATINIB AP26113 ; ACCURATE DOCKING ; C797S RESISTANCE ; T790M MUTATION ; DISCOVERY ; MUTANT ; POTENT ; OSIMERTINIB ; AZD9291 |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000802633700028 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309346]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xie, Hua; Lu, Xiaoyun; Ding, Ke |
| 作者单位 | 1.Jinan Univ, Huaqiao Hosp, Int Cooperat Lab Tradit Chinese Med Modernizat &, Minist Educ MOE,Sch Pharm,Guangzhou City Key Lab, Guangzhou 510632, Peoples R China; 2.Jinan Univ, Affiliated Hosp 1, Huaqiao Hosp, Guangzhou 510632, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; 5.Qingdao Univ, Coll Med, Inst Translat Med, Qingdao 266021, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China; 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 8.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 | Chen, Hao,Lai, Mengzhen,Zhang, Tao,et al. Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(9):6840-6858. |
| APA | Chen, Hao.,Lai, Mengzhen.,Zhang, Tao.,Chen, Yuqing.,Tong, Linjiang.,...&Ding, Ke.(2022).Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations.JOURNAL OF MEDICINAL CHEMISTRY,65(9),6840-6858. |
| MLA | Chen, Hao,et al."Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-GenerationEpidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations".JOURNAL OF MEDICINAL CHEMISTRY 65.9(2022):6840-6858. |
入库方式： OAI收割
来源：上海药物研究所
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