9VLM

The X-RAY co-crystal structure of human FGFR2 and covalent inhibitor 10a

This is a non-PDB format compatible entry.

Summary for 9VLM

• Entry DOI: 10.2210/pdb9vlm/pdb
• Descriptor: Fibroblast growth factor receptor 2, ~{N}-[3-[2-[[3-[2-(dimethylamino)ethylsulfamoylmethyl]phenyl]amino]pyrimidin-4-yl]-1-methyl-indol-6-yl]propanamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: fgfr2, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70749.74

Authors

Chen, X.J.,Liu, X.R.,Zhang, L.,Chen, Y.H. (deposition date: 2025-06-25, release date: 2026-05-06)

Primary citation

Zhu, W.,Chen, X.,Li, X.,Lin, J.,Lin, X.,Liu, X.,Deng, W.,Song, X.,Tu, Z.,Patterson, A.V.,Smaill, J.B.,Chen, Y.,Lu, X.
Structure-Based Design of 4-(1-Methyl-1 H -indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors.
J.Med.Chem., 69:5199-5218, 2026

PubMed Abstract: Aberrant fibroblast growth factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1-indol-3-yl)pyrimidin-2-amine derivatives as the first covalent FGFR3 selective inhibitors. The representative compound displayed high potency against FGFR3 (IC = 6.8 nM) and 5-60-fold selectivity over FGFR1/2/4. It was also effective against the common clinically acquired FGFR3 resistance mutation with an IC value of 19.2 nM. Furthermore, exhibited strong antiproliferative effects in FGFR3-driven RT112/84 cells (IC = 9.2 nM). Structural characterization using MALDI-TOF-MS and X-ray crystallography confirmed covalent binding of to FGFR3. Compound also showed significant antitumor efficacy in the RT112/84 bladder cancer xenograft model, offering a promising compound to address both selectivity and resistance in FGFR3-targeted therapy.

PubMed: 41648938
DOI: 10.1021/acs.jmedchem.5c02552

Experimental method

X-RAY DIFFRACTION (2.26 Å)