Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation
文献类型：期刊论文
| 作者 | Hu, Shiliang6; Tong, Linjiang7; Qin, Qiao6; Wen, Jiaxin1,7,8; Li, Yan7; Feng, Fang7; Wu, Kunzhong2; Zhou, Yang6; Shang, Jinsai2; Wang, Junjian5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2024-11-13 |
| 卷号 | 67期号:22页码:20531-20558 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.4c01975 |
| 通讯作者 | Xie, Hua(hxie@simm.ac.cn) ; Lu, Xiaoyun(luxy2016@jnu.edu.cn) |
| 英文摘要 | Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFRT790M/C797S mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFRT790M/C797S inhibitors. The representative compound 21v potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 2.3 nM and 12.5 nM, respectively, and exhibited antiproliferative activity against Ba/F3-EGFR19del/T790M/C797S and Ba/F3-EGFRL858R/T790M/C797S cells with IC50 values of 41 and 52 nM, respectively. Further, 21v inhibited proliferation of the EGFR19del/T790M/C797S mutant PC-9-OR NSCLC cell line with an IC50 value of 56 nM and displayed selectivity over parental Ba/F3 and A431 cells. Moreover, 21v exhibited antitumor efficacy in a Ba/F3-EGFR19del/T790M/C797S xenograft model. This study provides a promising macrocyclic lead for anticancer drug discovery overcoming EGFRC797S mutation mediated resistance in NSCLC patients. |
| WOS关键词 | ACQUIRED-RESISTANCE ; LUNG-CANCER ; DISCOVERY ; POTENT ; 1ST |
| 资助项目 | State Key Laboratory of Respiratory Disease[2024B1515040007] ; Changjiang Scholars Award Program of Ministry of Education, Guangdong Basic and Applied Basic Research Foundation[2022B515130008] ; Guangdong Basic and Applied Basic Research Foundation[82273948] ; National Natural Science Foundation of China[2021B0909050003] ; High-Level Innovative Research Institute, Department of Science and Technology of Guangdong Province[GZNL2023A02012] ; Major Program of Guangzhou National Laboratory[SKLRD-OP-202313] ; Major Program of Guangzhou National Laboratory[SKLRD-OP-202506] ; Open Project of State Key Laboratory of Respiratory Disease[2020B1212060034] ; Open Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation ; High-Performance Public Computing Service Platform of Jinan University |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001353988700001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314412]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xie, Hua; Lu, Xiaoyun |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Guangzhou Med Univ, Sch Basic Med Sci, Guangzhou Natl Lab, Guangzhou 511436, Peoples R China 3.Guangzhou Med Univ, Sch Basic Med Sci, State Key Lab Resp Dis, Guangzhou 511436, Peoples R China 4.Jinan Univ, Guangdong Prov Gen Hosp 2, Dept Hematol, Guangzhou 510632, Peoples R China 5.Sun Yat Sen Univ, Sch Pharmaceut Sci, Balance Based Drug Discovery Lab, Guangzhou 510006, Peoples R China 6.Jinan Univ, Sch Pharm,Guangzhou City Key Lab Precis Chem Drug, State Key Lab Bioact Mol & Druggabil Assessment, Int Cooperat Lab Tradit Chinese Med Modernizat & I, Guangzhou 510632, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, 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 | Hu, Shiliang,Tong, Linjiang,Qin, Qiao,et al. Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(22):20531-20558. |
| APA | Hu, Shiliang.,Tong, Linjiang.,Qin, Qiao.,Wen, Jiaxin.,Li, Yan.,...&Lu, Xiaoyun.(2024).Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation.JOURNAL OF MEDICINAL CHEMISTRY,67(22),20531-20558. |
| MLA | Hu, Shiliang,et al."Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation".JOURNAL OF MEDICINAL CHEMISTRY 67.22(2024):20531-20558. |
入库方式： OAI收割
来源：上海药物研究所
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