7ZY6

Identification of M4205 a highly selective inhibitor of cKIT mutations for unresectable metastatic or recurrent GIST

7ZY6 の概要

• エントリーDOI: 10.2210/pdb7zy6/pdb
• 分子名称: HUMAN PROTO-ONCOGENE C-KIT, 5-imidazo[1,2-a]pyridin-3-yl-~{N}-[(1~{R})-1-(6-pyrrolidin-1-ylpyridin-3-yl)ethyl]pyridin-3-amine (3 entities in total)
• 機能のキーワード: tyrosine-protein kinase, ckit, transferase
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37562.43

構造登録者

Graedler, U.,Lammens, A. (登録日: 2022-05-24, 公開日: 2023-02-22, 最終更新日: 2024-02-07)

主引用文献

Blum, A.,Dorsch, D.,Linde, N.,Brandstetter, S.,Buchstaller, H.P.,Busch, M.,Glaser, N.,Gradler, U.,Ruff, A.,Petersson, C.,Schieferstein, H.,Sherbetjian, E.,Esdar, C.
Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors.
J.Med.Chem., 66:2386-2395, 2023

PubMed Abstract: The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under treatment and relapse is observed. Several additional KIT inhibitors have been approved; still, there is a high unmet need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants. An imidazopyridine hit featuring excellent kinase selectivity was identified in a high-throughput screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42). This molecule has a superior profile compared to approved drugs, suggesting a best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations.

PubMed: 36728508
DOI: 10.1021/acs.jmedchem.2c00851

実験手法

X-RAY DIFFRACTION (3.09 Å)