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Discovery of roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4

Fairhurst, Robin and Knoepfel, Thomas and Buschmann, Nicole and Leblanc, Catherine and Mah, Robert and Todorov, Milen and Nimsgern, Pierre and Ripoche, Sebastien and Niklaus, Michel and Warin, Nicolas and Luu, Van Huy and Madoerin, Mario and Wirth, Jasmin and Graus Porta, Diana and Weiss, Andreas and Kiffe, Michael and Wartmann, Markus and Kinyamu-Akunda, Jacqueline and Sterker, Dario and Stamm, Christelle and Adler, Flavia and Buhles, Alexandra and Schadt, Heiko and Couttet, Philippe and Blank, Jutta and Galuba, Inga and Trappe, Joerg and Voshol, Johannes and Ostermann, Nils and Zou, Chao and Berghausen, Joerg and Del Rio Espinola, Alberto and 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

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