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Structure-based design of a dual-warhead covalent inhibitor 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, China.

Communications Chemistry
|January 25, 2023
PubMed

Insights

Researchers developed CXF-009, a novel dual-warhead covalent inhibitor targeting two key cysteines in fibroblast growth factor receptor 4 (FGFR4). This inhibitor shows promise for treating hepatocellular carcinoma (HCC) and overcoming drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling is implicated in various cancers, including hepatocellular carcinoma (HCC).
  • FGFR4 is a validated therapeutic target for HCC treatment.
  • Existing covalent inhibitors target single cysteine residues (Cys477 or Cys552) in FGFR4.

Purpose of the Study:

  • To design and synthesize a novel dual-warhead covalent inhibitor targeting both Cys477 and Cys552 of FGFR4.
  • To characterize the binding mode and inhibitory activity of the novel inhibitor.
  • To evaluate the potential of the inhibitor to overcome drug resistance mutations.

Main Methods:

  • Design and synthesis of a dual-warhead covalent inhibitor, CXF-009.
  • Cocrystallization of FGFR4 with CXF-009 to determine the binding structure.
  • Biochemical assays to assess selectivity against FGFR1-3 and other kinases.
  • Inhibition assays using wild-type and single-cysteine mutant FGFR4 (FGFR4(C477A), FGFR4(C552A)).

Main Results:

  • CXF-009 demonstrated a dual-warhead covalent binding mode, targeting both Cys477 and Cys552 of FGFR4.
  • The inhibitor exhibited high selectivity for FGFR4 over FGFR1-3 and other kinases.
  • CXF-009 effectively inhibited single-cysteine mutants FGFR4(C477A) and FGFR4(C552A).
  • This represents the first reported inhibitor forming dual-warhead covalent bonds with two cysteine residues in FGFR4.

Conclusions:

  • CXF-009 is a novel dual-warhead covalent inhibitor of FGFR4.
  • This inhibitor has the potential to overcome drug-resistant FGFR4 mutations in HCC.
  • CXF-009 serves as a promising lead compound for developing new anticancer therapeutics targeting the FGF19/FGFR4 pathway.

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