9UHI

FGFR1 kinase domain with a covalent inhibitor 9o

This is a non-PDB format compatible entry.

Summary for 9UHI

• Entry DOI: 10.2210/pdb9uhi/pdb
• Descriptor: Fibroblast growth factor receptor 1, ~{N}-[1-methyl-3-[3-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]quinoxalin-5-yl]indol-6-yl]propanamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: fibroblast growth factor receptor 1, transferase inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 72028.56

Authors

Chen, X.J.,Chen, Y.H. (deposition date: 2025-04-14, release date: 2025-09-24, Last modification date: 2025-10-08)

Primary citation

Deng, W.,Chen, X.,Yan, L.,Xiang, S.,Song, X.,Zhang, L.,Li, X.,Zhu, W.,Pei, J.,Lin, X.,Patterson, A.V.,Smaill, J.B.,Li, B.,Tu, Z.,Zhou, Y.,Chen, Y.,Lu, X.
Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1 H -indole-3-yl)-5 H -pyrrolo[2,3- b ]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance.
J.Med.Chem., 68:19415-19437, 2025

PubMed Abstract: Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1-indole-3-yl)-5-pyrrolo[2,3-]pyrazine derivatives as covalent pan-FGFR inhibitors targeting both wild-type and gatekeeper mutants. Compound demonstrated potent nanomolar inhibitory activity against FGFR1-3 and gatekeeper mutants in biochemical and cellular assays. Structural characterization using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) and X-ray crystallography confirmed covalent binding of to FGFR1. Additionally, showed significant in vivo antitumor efficacy in nude mice bearing the RT112 bladder cancer xenograft model. These findings establish as a promising lead for further development of FGFR-targeted anticancer therapies.

PubMed: 40921092
DOI: 10.1021/acs.jmedchem.5c01594

Experimental method

X-RAY DIFFRACTION (1.76 Å)