Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.,Journal of Medicinal Chemistry

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Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-15 , DOI: 10.1021/acs.jmedchem.0c00870
Jonas Lategahn _{1,

2} , Julia Hardick _{1,

2} , Tobias Grabe _{1,

2} , Janina Niggenaber _{1,

2} , Kirujan Jeyakumar _{1,

2} , Marina Keul _{1,

2} , Hannah L Tumbrink ₁ , Christian Becker ₁ , Luke Hodson _{1,

3} , Tonia Kirschner _{1,

2} , Philip Klövekorn ₁ , Julia Ketzer _{4,

5} , Matthias Baumann ₆ , Susanne Terheyden ₆ , Anke Unger ₆ , Jörn Weisner _{1,

2} , Matthias P Müller _{1,

2} , Willem A L van Otterlo ₃ , Sebastian Bauer _{4,

5} , Daniel Rauh _{1,

2}

Affiliation

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.

中文翻译：

用共价抑制剂靶向Her2-insYVMA-一种集中的化合物筛选和基于结构的设计方法。

突变或扩增的Her2充当非小细胞肺癌的驱动因子，或介导抵抗小分子抑制剂对其家族成员表皮生长因子受体的抑制作用。迄今为止，缺乏可用于临床常规的靶向Her2的小分子抑制剂，因此，进行了新型抑制剂的开发。在这项研究中，完善的吡咯并嘧啶支架被结构化主题修饰，该结构主题来自对1600多种化合物的筛选活动，这些化合物被应用于野生型Her2及其突变体Her2-A775_G776insYVMA。设计所得的抑制剂以在Her2的结合位点共价靶向反应性半胱氨酸，并通过利用一组获得的复杂晶体结构的基于结构的药物设计进一步优化。

更新日期：2020-10-22

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