Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4 PMID: 32930584

ADC Targets in Oncology

2026-04-10

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

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.