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

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; Jörg Trappe; Johannes Voshol; Nils Ostermann; Chao Zou; Jörg Berghausen; Alberto Del Rio Espinola; Wolfgang Jahnke; Pascal Furet

doi:10.1021/acs.jmedchem.0c01019

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. Epub 2020 Oct 1.

Authors

Robin A Fairhurst¹, Thomas Knoepfel¹, Nicole Buschmann¹, Catherine Leblanc¹, Robert Mah¹, Milen Todorov¹, Pierre Nimsgern¹, Sebastien Ripoche¹, Michel Niklaus¹, Nicolas Warin¹, Van Huy Luu¹, Mario Madoerin¹, Jasmin Wirth¹, Diana Graus-Porta¹, Andreas Weiss¹, Michael Kiffe¹, Markus Wartmann¹, Jacqueline Kinyamu-Akunda¹, Dario Sterker¹, Christelle Stamm¹, Flavia Adler¹, Alexandra Buhles¹, Heiko Schadt¹, Philippe Couttet¹, Jutta Blank¹, Inga Galuba¹, Jörg Trappe¹, Johannes Voshol¹, Nils Ostermann¹, Chao Zou¹, Jörg Berghausen¹, Alberto Del Rio Espinola¹, Wolfgang Jahnke¹, Pascal Furet¹

Affiliation

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.

MeSH terms

Amino Acid Sequence
Animals
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cysteine / chemistry
Dogs
Drug Design
Half-Life
Hepatocytes / cytology
Hepatocytes / drug effects
Hepatocytes / metabolism
Liver Neoplasms / drug therapy
Mice
Microsomes, Liver / metabolism
Molecular Dynamics Simulation
Piperazines / chemistry*
Piperazines / metabolism
Piperazines / pharmacology
Piperazines / therapeutic use
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyridines / chemistry*
Pyridines / metabolism
Pyridines / pharmacology
Pyridines / therapeutic use
Rats
Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 4 / metabolism
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Piperazines
Protein Kinase Inhibitors
Pyridines
Receptor, Fibroblast Growth Factor, Type 4
Cysteine
roblitinib