Robin A. Fairhurst, Thomas Knoepfel, Nicole Buschmann, Catherine Leblanc, Robert Mah, Milen Todorov, Pierre Nimsgern, Sebastien Ripoche, Michel Niklaus, Nicolas Warin, Van Huy Luu, Mario Madoerin, Jasmin Wirth, Diana Graus-Porta, Andreas Weiss, Michael Kiffe, Markus Wartmann, Jacqueline Kinyamu-Akunda, Dario Sterker, Christelle Stamm, Flavia Adler, Alexandra Buhles, Heiko Schadt, Philippe Couttet, Jutta Blank, Inga Galuba, Joerg Trappe, Johannes Voshol, Nils Ostermann, Chao Zou, Joerg Berghausen, Alberto Del Rio Espinola, Wolfgang Jahnke, and Pascal Furet
Journal of Medicinal Chemistry 2020
DOI: 10.1021/acs.jmedchem.0c01019
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.
