8D76

Crystal Structure of EGFR LRTM with compound 24

8D76 の概要

• エントリーDOI: 10.2210/pdb8d76/pdb
• 分子名称: Epidermal growth factor receptor, GLYCEROL, (3S,4R)-3-fluoro-1-(4-{[8-{3-[(methanesulfonyl)methyl]azetidin-1-yl}-5-(propan-2-yl)-2,7-naphthyridin-3-yl]amino}pyrimidin-2-yl)-3-methylpiperidin-4-ol, ... (4 entities in total)
• 機能のキーワード: protein kinase, inhibitor, kinase domain, mutation, signaling protein
• 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: 81235.43

構造登録者

Kim, J.L. (登録日: 2022-06-07, 公開日: 2022-07-27, 最終更新日: 2023-10-18)

主引用文献

Eno, M.S.,Brubaker, J.D.,Campbell, J.E.,De Savi, C.,Guzi, T.J.,Williams, B.D.,Wilson, D.,Wilson, K.,Brooijmans, N.,Kim, J.,Ozen, A.,Perola, E.,Hsieh, J.,Brown, V.,Fetalvero, K.,Garner, A.,Zhang, Z.,Stevison, F.,Woessner, R.,Singh, J.,Timsit, Y.,Kinkema, C.,Medendorp, C.,Lee, C.,Albayya, F.,Zalutskaya, A.,Schalm, S.,Dineen, T.A.
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.
J.Med.Chem., 65:9662-9677, 2022

PubMed Abstract: While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound ) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

PubMed: 35838760
DOI: 10.1021/acs.jmedchem.2c00704

実験手法

X-RAY DIFFRACTION (2.4 Å)