Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation
文献类型：期刊论文
| 作者 | Hao, Yongjia1; Wang, Xia1; Zhang, Tao2; Sun, Deheng1; Tong, Yi1; Xu, Yuqiong1; Chen, Haiyang1; Tong, Linjiang2; Zhu, Lili1; Zhao, Zhenjiang1 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-08-11 |
| 卷号 | 59期号:15页码:7111-7124 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6b00403 |
| 文献子类 | Article |
| 英文摘要 | EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR. Finally, the most representative compound 17d was identified. This work, demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR(L858R/T790M) over EGFR(WT), which may play an important role in designing new classes of mutant-selective EGFR inhibitors. |
| WOS关键词 | CELL LUNG-CANCER ; MOLECULE KINASE INHIBITORS ; BIOLOGICAL EVALUATION ; METHIONINE(790) MUTANT ; ACQUIRED-RESISTANCE ; COVALENT INHIBITORS ; DRUG-RESISTANCE ; GEFITINIB ; DESIGN ; THREONINE(790) |
| 资助项目 | Fundamental Research Funds for the Central Universities[00000000] ; National Natural Science Foundation of China[21302054] ; National Natural Science Foundation of China[81222046] ; National Natural Science Foundation of China[81230076] ; Shanghai Committee of Science and Technology[14431902100] ; Shanghai Committee of Science and Technology[13ZR1453100] ; National Key Research and Development Program[2016YFA0502304] ; National S&T Major Project of China[2013ZX09507004] ; Twelfth Five-Year National Science & Technology Support Program[2012BAI29B06] ; Specialized Research Fund for the Doctoral Program of Higher Education[20130074110004] ; Innovation Program of Shanghai Municipal Education Commission[13SG32] ; Fok Ying Tung Education Foundation[141035] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000381452600009 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275926]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Xie, Hua; Xu, Yufang; Li, Honglin |
| 作者单位 | 1.East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn,Sch Pharm, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hao, Yongjia,Wang, Xia,Zhang, Tao,et al. Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(15):7111-7124. |
| APA | Hao, Yongjia.,Wang, Xia.,Zhang, Tao.,Sun, Deheng.,Tong, Yi.,...&Li, Honglin.(2016).Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.JOURNAL OF MEDICINAL CHEMISTRY,59(15),7111-7124. |
| MLA | Hao, Yongjia,et al."Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation".JOURNAL OF MEDICINAL CHEMISTRY 59.15(2016):7111-7124. |
入库方式： OAI收割
来源：上海药物研究所
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