azd4547 and Liver-Neoplasms

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.

Topics: Amino Acid Sequence; Animals; Binding Sites; Cell Line, Tumor; Cell Proliferation; Cysteine; Dogs; Drug Design; Half-Life; Hepatocytes; Liver Neoplasms; Mice; Microsomes, Liver; Molecular Dynamics Simulation; Piperazines; Protein Kinase Inhibitors; Pyridines; Rats; Receptor, Fibroblast Growth Factor, Type 4; Structure-Activity Relationship; Xenograft Model Antitumor Assays