7OZF

FGFR1 kinase domain (residues 458-765) with mutations C488A, C584S in complex with 19.

これはPDB形式変換不可エントリーです。

7OZF の概要

• エントリーDOI: 10.2210/pdb7ozf/pdb
• 分子名称: Fibroblast growth factor receptor 1, N-[6-(3-ethoxyphenyl)-1H-indazol-3-yl]benzamide, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: fgfr1, inhibitor, receptor tyrosine kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71400.73

構造登録者

Trinh, C.H.,Turner, L.D.,Fishwick, C.W.G. (登録日: 2021-06-28, 公開日: 2021-12-01, 最終更新日: 2024-01-31)

主引用文献

Turner, L.D.,Trinh, C.H.,Hubball, R.A.,Orritt, K.M.,Lin, C.C.,Burns, J.E.,Knowles, M.A.,Fishwick, C.W.G.
From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.
J.Med.Chem., 65:1481-1504, 2022

PubMed Abstract: Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.

PubMed: 34780700
DOI: 10.1021/acs.jmedchem.1c01163

実験手法

X-RAY DIFFRACTION (1.82 Å)