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

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.