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

  • J Med Chem. 2020 Nov 12;63(21):12542-12573. doi: 10.1021/acs.jmedchem.0c01019.
Robin A Fairhurst  1 ,  Thomas Knoepfel  1 ,  Nicole Buschmann  1 ,  Catherine Leblanc  1 ,  Robert Mah  1 ,  Milen Todorov  1 ,  Pierre Nimsgern  1 ,  Sebastien Ripoche  1 ,  Michel Niklaus  1 ,  Nicolas Warin  1 ,  Van Huy Luu  1 ,  Mario Madoerin  1 ,  Jasmin Wirth  1 ,  Diana Graus-Porta  1 ,  Andreas Weiss  1 ,  Michael Kiffe  1 ,  Markus Wartmann  1 ,  Jacqueline Kinyamu-Akunda  1 ,  Dario Sterker  1 ,  Christelle Stamm  1 ,  Flavia Adler  1 ,  Alexandra Buhles  1 ,  Heiko Schadt  1 ,  Philippe Couttet  1 ,  Jutta Blank  1 ,  Inga Galuba  1 ,  Jörg Trappe  1 ,  Johannes Voshol  1 ,  Nils Ostermann  1 ,  Chao Zou  1 ,  Jörg Berghausen  1 ,  Alberto Del Rio Espinola  1 ,  Wolfgang Jahnke  1 ,  Pascal Furet  1
Affiliations
  • 1. Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 32930584 DOI: 10.1021/acs.jmedchem.0c01019
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 summarized which made use of both rational and unbiased screening approaches. The optimization 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 optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.

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