9GC4

Highly optimized CNS penetrant inhibitors of EGFR Exon20 Insertion Mutations

これはPDB形式変換不可エントリーです。

9GC4 の概要

• エントリーDOI: 10.2210/pdb9gc4/pdb
• 分子名称: Epidermal growth factor receptor, 1-[2-[3-(3-chloranyl-6-fluoranyl-pyridin-2-yl)oxyphenyl]-3-pyrimidin-4-yl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one (3 entities in total)
• 機能のキーワード: egfr, exon20, npg, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 114253.54

構造登録者

Hargreaves, D. (登録日: 2024-08-01, 公開日: 2025-02-12, 最終更新日: 2025-02-26)

主引用文献

McCoull, W.,Thomson, C.,Braybrooke, E.,Chan, C.,Colclough, N.,Cortes Gonzalez, M.A.,Cosulich, S.,Davies, N.L.,Floc'h, N.,Greenwood, R.,Hargreaves, D.,Huang, P.,Hunt, T.A.,Johnson, T.,Johnstrom, P.,Kettle, J.G.,Kondrashov, M.,Kostomiris, D.H.,Li, S.,Lister, A.,Martin, S.,McKerrecher, D.,McLean, N.,Nissink, J.W.M.,Orme, J.P.,Orwig, P.,Packer, M.J.,Pearson, S.,Qin, L.,Felisberto-Rodrigues, C.,Savoca, A.,Schou, M.,Stokes, S.,Swaih, A.M.,Talbot, S.,Tucker, M.J.,Ward, R.A.,Wadforth, E.,Wang, C.,Wilson, J.,Yang, Y.
Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.
J.Med.Chem., 68:3700-3748, 2025

PubMed Abstract: Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.

PubMed: 39869768
DOI: 10.1021/acs.jmedchem.4c02811

実験手法

X-RAY DIFFRACTION (2.415 Å)