Fairhurst, Robin, Knoepfel, Thomas, Buschmann, Nicole, Leblanc, Catherine, Mah, Robert, Todorov, Milen, Nimsgern, Pierre, Ripoche, Sebastien, Niklaus, Michel, Warin, Nicolas, Luu, Van Huy, Madoerin, Mario, Wirth, Jasmin, Graus Porta, Diana, Weiss, Andreas, Kiffe, Michael, Wartmann, Markus, Kinyamu-Akunda, Jacqueline, Sterker, Dario, Stamm, Christelle, Adler, Flavia, Buhles, Alexandra, Schadt, Heiko, Couttet, Philippe, Blank, Jutta, Galuba, Inga, Trappe, Joerg, Voshol, Johannes, Ostermann, Nils, Zou, Chao, Berghausen, Joerg, Del Rio Espinola, Alberto, Jahnke, Wolfgang and Furet, Pascal (2020) Discovery of roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. Journal of medicinal chemistry, 63 (21). pp. 12542-12573. ISSN 0022-2623

Abstract

FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly-conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarised which made use of both rationale and unbiased screening approaches. The optimisation of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimisation are improving the FGFR4 potency, metabolic stability and solubility leading ultimately to the highly-selective first-in-class clinical candidate roblitinib.

Item Type:	Article
Keywords:	kinase inhibitor, FGFR4, reversible-covalent inhibitor, hepatocellular carcinoma, FGF401, roblitinib, binding kinetics
Date Deposited:	19 Jan 2021 00:45
Last Modified:	19 Jan 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42502