8PO3

Discovery and Optimisation of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Compound 18 bound to EGFR[V948R]

8PO3 の概要

• エントリーDOI: 10.2210/pdb8po3/pdb
• 分子名称: Epidermal growth factor receptor, 2-methyl-5-[[3-[1-[(3~{S})-1-propanoylpyrrolidin-3-yl]-4-pyridin-4-yl-pyrazol-3-yl]phenoxy]methyl]-3~{H}-isoindol-1-one (3 entities in total)
• 機能のキーワード: egfr, exon 20 insertion, non-small cell lung cancer, oncology, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38115.01

構造登録者

Hargreaves, D. (登録日: 2023-07-03, 公開日: 2024-06-05, 最終更新日: 2024-11-06)

主引用文献

Thomson, C.,Barton, P.,Braybrooke, E.,Colclough, N.,Dong, Z.,Evans, L.,Floc'h, N.,Guerot, C.,Hargreaves, D.,Khurana, P.,Li, S.,Li, X.,Lister, A.,McCoull, W.,McWilliams, L.,Orme, J.P.,Packer, M.J.,Swaih, A.M.,Ward, R.A.,Winlow, P.,Ye, Y.
Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.
J.Med.Chem., 67:8988-9027, 2024

PubMed Abstract: Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of . Compound is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (), indicating that may have lower EGFR wild-type associated toxicity.

PubMed: 38770784
DOI: 10.1021/acs.jmedchem.4c00227

実験手法

X-RAY DIFFRACTION (2.13 Å)