7ZY6

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

Summary for 7ZY6

• Entry DOI: 10.2210/pdb7zy6/pdb
• Descriptor: 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)
• Functional Keywords: tyrosine-protein kinase, ckit, transferase
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 37562.43

Authors

Graedler, U.,Lammens, A. (deposition date: 2022-05-24, release date: 2023-02-22, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.09 Å)