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Updated: Dec 9, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth

Robin A Fairhurst1, Thomas Knoepfel1, Nicole Buschmann1

  • 1Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.

Journal of Medicinal Chemistry
|September 15, 2020
PubMed

Insights

Researchers developed roblitinib, a selective FGFR4 inhibitor, to treat hepatocellular carcinoma. This targeted therapy exploits a unique cysteine in FGFR4, offering a new treatment avenue for this cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Fibroblast Growth Factor 19 (FGF19) signaling via the FGFR4/β-klotho receptor complex drives growth in some hepatocellular carcinomas (HCC).
  • Selective inhibition of Fibroblast Growth Factor Receptor 4 (FGFR4) presents a promising therapeutic strategy for these specific HCC cases.

Purpose of the Study:

  • To identify and optimize selective FGFR4 inhibitors targeting a unique cysteine residue (C552) in the ATP-binding site.
  • To develop a first-in-class clinical candidate for FGFR4-driven hepatocellular carcinoma.

Main Methods:

  • Kinome-wide sequence alignment to identify conserved and unique residues in FGFR4.
  • Exploration of rational and unbiased screening approaches to discover inhibitor starting points.
  • Optimization of a 2-formylquinoline amide series utilizing a reversible-covalent interaction with C552.

Main Results:

  • A poorly conserved cysteine at position 552 in FGFR4 was identified as a potential target.
  • A 2-formylquinoline amide series was optimized, forming a hemithioacetal with C552.
  • The optimization successfully improved potency, metabolic stability, and solubility.

Conclusions:

  • Roblitinitib, a highly selective FGFR4 inhibitor, was developed as a first-in-class clinical candidate.
  • Targeting C552 offers a specific strategy for inhibiting FGFR4 in relevant cancers.
  • This work provides a foundation for novel targeted therapies in hepatocellular carcinoma.

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