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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4

Xiaojuan Chen1, Huiliang Li2, Qianmeng Lin1

  • 1Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

European Journal of Medicinal Chemistry
|March 3, 2024
PubMed

Insights

A novel covalent inhibitor, CXF-007, effectively targets fibroblast growth factor receptor 4 (FGFR4) and its mutants. This discovery offers a promising new strategy for developing anticancer therapies against solid tumors driven by aberrant FGF19/FGFR4 signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Aberrant fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling drives tumorigenesis in various solid tumors.
  • FGFR4 represents a significant therapeutic target for anticancer drug development.

Purpose of the Study:

  • To design and synthesize novel covalent inhibitors targeting FGFR4.
  • To evaluate the inhibitory activity and antitumor potential of these compounds against FGFR4 and its mutants.

Main Methods:

  • Synthesis of bis-acrylamide covalent FGFR4 inhibitors.
  • In vitro evaluation of inhibitory activity against FGFRs and FGFR4 mutants.
  • Mass spectrometry and crystal structure analysis to confirm covalent binding.
  • Assessment of antitumor activity in hepatocellular carcinoma and breast cancer cell lines.

Main Results:

  • CXF-007 demonstrated potent and selective inhibition of FGFR4 and its cysteine mutants.
  • Covalent binding of CXF-007 to Cys552 of FGFR4 and Cys488 of FGFR1 was confirmed.
  • CXF-007 exhibited significant antitumor effects in relevant cancer cell lines via sustained FGFR4 pathway inhibition.

Conclusions:

  • CXF-007 is a novel covalent FGFR4 inhibitor with potential to overcome drug-induced mutations.
  • This compound offers a promising new therapeutic strategy for cancers driven by aberrant FGF19/FGFR4 signaling.
Keywords:
Antitumor activityBreast cancerCovalent inhibitorsFGFR4FGFR4 cysteine mutants

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