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通过基于结构的从头设计发现对 d746-750/T790M/C797S 突变体具有选择性的表皮生长因子受体抑制剂。

Discovery of EGF Receptor Inhibitors That Are Selective for the d746-750/T790M/C797S Mutant through Structure-Based de Novo Design.

机构信息

Department of Bioscience and Biotechnology, Sejong University, Seoul, 143-747, Korea.

Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.

出版信息

Angew Chem Int Ed Engl. 2017 Jun 19;56(26):7634-7638. doi: 10.1002/anie.201703389. Epub 2017 May 22.

DOI:10.1002/anie.201703389
PMID:28493467
Abstract

Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.

摘要

通过双轨虚拟筛选和从头设计发现了针对 d746-750/T790M/C797S 突变的下一代表皮生长因子受体 (EGFR) 抑制剂。使用 2-芳基-4-氨基喹唑啉作为分子核心，并采用涉及适当去水项的改良结合能函数，鉴定出了许多纳摩尔抑制剂，这为高抑制 d746-750/T790M/C797S 突变体的关键原则提供了重要的结构见解。此外，这些 EGFR 抑制剂中的一些对 d746-750/T790M/C797S 突变体的选择性大于野生型 1000 倍以上，对突变体也具有纳摩尔活性。

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