10OO

FGFR2 mutant D650V with compound 4 (AZD3463)

This is a non-PDB format compatible entry.

Summary for 10OO

• Entry DOI: 10.2210/pdb10oo/pdb
• Related: 10OQ 10OU
• Descriptor: Fibroblast growth factor receptor 2, (4P)-N-[4-(4-aminopiperidin-1-yl)-2-methoxyphenyl]-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine, GLYCEROL, ... (5 entities in total)
• Functional Keywords: fgfr2, fgfr, fibroblast growth factor receptor, tyrosine kinase, resistance mutations, azd3463, compound 4, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75723.69

Authors

Hoffman, I.D.,Nelson, K.J. (deposition date: 2026-01-29, release date: 2026-04-15)

Primary citation

Hudkins, R.L.,Allen, E.,Iyer, S.,Balcer, A.,Neal, M.,Ye, Q.,Rideout, M.,Frye, C.B.,Nelson, K.J.,Hoffman, I.D.,Starrett, J.H.,Harris, T.,Swanson, R.V.,Bensen, D.C.
Structure-Based Design of a Novel Covalent 4-(1-Methylindol-3-yl)pyrimidin-2-amine Series Targeting FGFR2 Resistance Mutations.
J.Med.Chem., 69:8614-8627, 2026

PubMed Abstract: Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead showed favorable potency, ADME properties, and demonstrated proof-of-concept efficacy in an FGFR2-amplified xenograft model comparable with the standard of care.

PubMed: 41913484
DOI: 10.1021/acs.jmedchem.6c00514

Experimental method

X-RAY DIFFRACTION (1.85 Å)