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Updated: May 3, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Discovery of novel FGFR4 inhibitors through a build-up fragment strategy

Jihyung Kim1,2, Chang Gyun Im1,2, Kyujin Oh1

  • 1College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.

Journal of Enzyme Inhibition and Medicinal Chemistry
|April 24, 2024
PubMed

Insights

Researchers discovered a new potent inhibitor, compound 4c, targeting FGFR4 to treat hepatocellular carcinoma (HCC). This fragment-based drug discovery approach shows promise for developing effective HCC therapies.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Hepatocellular carcinoma (HCC) is a significant global health concern and a primary cause of cancer mortality.
  • Fibroblast Growth Factor Receptor 4 (FGFR4) plays a crucial role in HCC pathogenesis, identifying it as a key therapeutic target.

Purpose of the Study:

  • To develop a novel strategy for identifying potent and selective FGFR4 inhibitors.
  • To discover new chemical entities for the potential treatment of hepatocellular carcinoma.

Main Methods:

  • Employed a fragment-based drug discovery approach, sequentially adding fragments to a common warhead.
  • Synthesized and evaluated a series of novel compounds for FGFR4 inhibitory activity.

Main Results:

  • Identified compound 4c as a potent FGFR4 inhibitor with an IC50 of 33 nM.
  • Compound 4c demonstrated high selectivity across the FGFR family, indicating specificity for the target.

Conclusions:

  • The developed fragment-based approach is effective for discovering potent FGFR4 inhibitors.
  • Compound 4c represents a promising lead for further optimization in the development of novel HCC therapeutics.
Keywords:
FGFR4fragmenthit identificationkinase inhibitorsmall molecule

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