5NUD

FIBROBLAST GROWTH FACTOR RECEPTOR 4 KINASE DOMAIN (449-753) IN COMPLEX WITH IRREVERSIBLE LIGAND CGA159527

5NUD の概要

• エントリーDOI: 10.2210/pdb5nud/pdb
• 分子名称: Fibroblast growth factor receptor 4, 3-chloranyl-~{N}-(3-nitropyridin-2-yl)-5-(trifluoromethyl)pyridin-2-amine (3 entities in total)
• 機能のキーワード: other, hormone-growth factor complex, hormone/growth factor
• 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: 69374.66

構造登録者

Zou, C. (登録日: 2017-04-29, 公開日: 2018-04-04, 最終更新日: 2024-11-13)

主引用文献

Fairhurst, R.A.,Knoepfel, T.,Leblanc, C.,Buschmann, N.,Gaul, C.,Blank, J.,Galuba, I.,Trappe, J.,Zou, C.,Voshol, J.,Genick, C.,Brunet-Lefeuvre, P.,Bitsch, F.,Graus-Porta, D.,Furet, P.
Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region.
Medchemcomm, 8:1604-1613, 2017

PubMed Abstract: A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.

PubMed: 30108871
DOI: 10.1039/c7md00213k

実験手法

X-RAY DIFFRACTION (2.5 Å)