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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 T790M是一种继发性突变，使携带原发致癌突变(如L858R和外显子19缺失)的EGFR激酶对包括易瑞沙和Tarceva在内的老一代药物产生抗药性。基于我们先前确定的EGFR T790M的晶体结构和针对共价抑制的聚焦小分子文库的筛选，我们成功地鉴定了一种新的支架，它可以有效地抑制携带T790M的突变体EGFR，而不抑制野生型EGFR。本结构研究旨在解决T790M与这些新发现的抑制剂的复杂结构，以帮助理解新支架良好专一性的分子基础，并促进新药的进一步改进。

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.