ly2874455 and Liver-Neoplasms

Hepatocellular carcinoma (HCC) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Aberrant fibroblast growth factor 19 (FGF19) signaling through fibroblast growth factor receptor 4 (FGFR4) has been identified as an oncogenic driver for a subset of patients with HCC. FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial. In this review, we summarize the latest developments in FGFR4 inhibitors, including the known pharmacophores, their binding mode, selectivity, and clinical implications, as well as the optimization strategy of introducing an acrylamide into a known pan-FGFR inhibitor targeting Cys552 of FGFR4 to provide selective covalent FGFR4 inhibitors.

Topics: Binding Sites; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Protein Structure, Tertiary; Receptor, Fibroblast Growth Factor, Type 4; Signal Transduction

Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target due to its transmission of the FGF19 signaling pathway, which is critical to hepatocellular carcinoma (HCC). Therefore, focusing on the specific Cys552 of FGFR4 subtype, we designed and synthesized a novel family of 1,6-naphthyridin-2(1

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Fibroblast Growth Factors; Humans; Liver Neoplasms; Naphthyridines; Receptor, Fibroblast Growth Factor, Type 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.

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