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2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4

Knoepfel, Thomas and Furet, Pascal and Mah, Robert and Buschmann, Nicole and Leblanc, Catherine and Ripoche, Sebastien and Graus Porta, Diana and Wartmann, Markus and Galuba, Inga (2018) 2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4. ACS Medicinal Chemistry Letters, 9 (3). pp. 215-220. ISSN 19485875

Abstract

As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity.

Item Type: Article
Keywords: 2-Formylpyridines binding kinetics fibroblast growth factor receptor 4 hepatocellular carcinoma kinase inhibitors reversible-covalent binders
Date Deposited: 14 Jul 2018 00:45
Last Modified: 14 Jul 2018 00:45
URI: https://oak.novartis.com/id/eprint/34446

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