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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 T790 M是一种继发性突变，使携带原发性致癌突变（如L 858 R和外显子19缺失）的EGFR激酶对老一代药物（包括易瑞沙和特罗凯）耐药。基于我们先前确定的EGFR T790 M晶体结构和针对共价抑制的聚焦小分子文库筛选，我们成功地鉴定了可以有效抑制携带突变EGFR的T790 M并且不抑制野生型EGFR的新支架。这项结构研究旨在解决T790 M与这些新发现的抑制剂的复杂结构，以帮助理解新支架的优异特异性的分子基础，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.