化学
小分子
铅化合物
表皮生长因子受体
半胱氨酸
共价键
突变体
立体化学
表皮生长因子受体抑制剂
生物化学
药理学
组合化学
酶
受体
体外
有机化学
基因
医学
作者
Jonas Lategahn,Julia Hardick,Tobias Grabe,Janina Niggenaber,Kirujan Jeyakumar,Marina Keul,Hannah L. Tumbrink,Christian Becker,Luke Hodson,Tonia Kirschner,Philip Klövekorn,Julia Ketzer,Matthias Baumann,Susanne Terheyden,Anke Unger,Jörn Weisner,Matthias Müller,Willem A. L. van Otterlo,Sebastian Bauer,Daniel Rauh
标识
DOI:10.1021/acs.jmedchem.0c00870
摘要
Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.
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