4RJ5

EGFR kinase (T790M/L858R) with inhibitor compound 5

4RJ5 の概要

• エントリーDOI: 10.2210/pdb4rj5/pdb
• 関連するPDBエントリー: 4RJ3 4RJ4 4RJ6 4RJ7 4RJ8
• 分子名称: Epidermal growth factor receptor, N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine (2 entities in total)
• 機能のキーワード: protein kinase, phosphotransfer catalyst, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37939.84

構造登録者

Eigenbrot, C.,Yu, C. (登録日: 2014-10-08, 公開日: 2014-11-26, 最終更新日: 2023-09-20)

主引用文献

Hanan, E.J.,Eigenbrot, C.,Bryan, M.C.,Burdick, D.J.,Chan, B.K.,Chen, Y.,Dotson, J.,Heald, R.A.,Jackson, P.S.,La, H.,Lainchbury, M.D.,Malek, S.,Purkey, H.E.,Schaefer, G.,Schmidt, S.,Seward, E.M.,Sideris, S.,Tam, C.,Wang, S.,Yeap, S.K.,Yen, I.,Yin, J.,Yu, C.,Zilberleyb, I.,Heffron, T.P.
Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.
J.Med.Chem., 57:10176-10191, 2014

PubMed Abstract: Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.

PubMed: 25383627
DOI: 10.1021/jm501578n

実験手法

X-RAY DIFFRACTION (3.1 Å)