ml7b00485_si_001.pdf (1.94 MB)
2‑Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4
journal contribution
posted on 2018-02-01, 00:00 authored by Thomas Knoepfel, Pascal Furet, Robert Mah, Nicole Buschmann, Catherine Leblanc, Sebastien Ripoche, Diana Graus-Porta, Markus Wartmann, Inga Galuba, Robin A. FairhurstAs
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.