CRYSTAL STRUCTURE OF DRUG-RESISTANT EGFR MUTANT IN COMPLEX WITH NEW INHIBITORS

与新抑制剂复合的耐药 EGFR 突变体的晶体结构

• 批准号: 8169315
• 负责人: MICHAEL J ECK
• 金额: $ 4.32万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169315
• 关键词: Complex; Computer Retrieval of Information on Scientific Projects Database; Drug resistance; Epidermal Growth Factor Receptor; Erlotinib; Exons; Funding; Gefitinib; Generations; Grant; Institution; Molecular; Mutation; Oncogenic; Pharmaceutical Preparations; Phosphotransferases; Research; Research Personnel; Resistance; Resources; Screening procedure; Source; Specificity; Structure; United States National Institutes of Health; base; inhibitor/antagonist; mutant; scaffold; small molecule libraries

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T790M is a secondary mutation that renders the EGFR kinase bearing the primary oncogenic mutations (such as L858R and deletions in exon 19) resistant to the old generation drugs including Iressa and Tarceva. Based on our previously determined EGFR T790M crystal structure and focused small molecule library screening for covalent inhibition, we were successful in identifying a new scaffold that can effectively inhibit the T790M bearing mutant EGFR and does not inhibit the wild-type EGFR. This structural study aimed to solve the complex structures of T790M with these newly identified inhibitors to help in understanding the molecular basis for the excellent specificity of the new scaffold and to facilitate further improvement of the new drug.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 T790M 是一种二次突变，使带有主要致癌突变（例如 L858R 和外显子 19 缺失）的 EGFR 激酶对易瑞沙和特罗凯等老一代药物产生耐药性。基于我们之前确定的EGFR T790M晶体结构和针对共价抑制的重点小分子库筛选，我们成功地鉴定了一种能够有效抑制带有T790M突变型EGFR且不抑制野生型EGFR的新支架。本结构研究旨在用这些新发现的抑制剂解决T790M的复杂结构，以帮助理解新支架优异特异性的分子基础，并有利于新药的进一步改进。