6TFU

Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 14d

6TFU の概要

• エントリーDOI: 10.2210/pdb6tfu/pdb
• 分子名称: Epidermal growth factor receptor, ~{N}-[3-[4-[[1-(phenylmethyl)indazol-5-yl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: her2, egfr, covalent inhibitors, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77287.18

構造登録者

Niggenaber, J.,Mueller, M.P.,Rauh, D. (登録日: 2019-11-14, 公開日: 2020-09-30, 最終更新日: 2024-10-16)

主引用文献

Lategahn, J.,Hardick, J.,Grabe, T.,Niggenaber, J.,Jeyakumar, K.,Keul, M.,Tumbrink, H.L.,Becker, C.,Hodson, L.,Kirschner, T.,Klovekorn, P.,Ketzer, J.,Baumann, M.,Terheyden, S.,Unger, A.,Weisner, J.,Muller, M.P.,van Otterlo, W.A.L.,Bauer, S.,Rauh, D.
Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach.
J.Med.Chem., 63:11725-11755, 2020

PubMed Abstract: 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.

PubMed: 32931277
DOI: 10.1021/acs.jmedchem.0c00870

実験手法

X-RAY DIFFRACTION (2 Å)