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Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region

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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.

Graphical abstract: Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region

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Publication details

The article was received on 27 Apr 2017, accepted on 28 May 2017 and first published on 08 Jun 2017


Article type: Research Article
DOI: 10.1039/C7MD00213K
Citation: Med. Chem. Commun., 2017, Advance Article
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    Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region

    R. A. Fairhurst, T. Knoepfel, C. Leblanc, N. Buschmann, C. Gaul, J. Blank, I. Galuba, J. Trappe, C. Zou, J. Voshol, C. Genick, P. Brunet-Lefeuvre, F. Bitsch, D. Graus-Porta and P. Furet, Med. Chem. Commun., 2017, Advance Article , DOI: 10.1039/C7MD00213K

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