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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 the First Novel Macrocycle-Based FGFR Inhibitors That Overcome

Shuang Xiang1, Xiaojuan Chen2, Jieying Lin1

  • 1Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.

Journal of Medicinal Chemistry
|January 6, 2026
PubMed

Insights

Researchers developed novel macrocycle-based inhibitors targeting Fibroblast Growth Factor Receptor (FGFR) pathways. These compounds effectively target both wild-type and resistant FGFR mutations, addressing a key challenge in cancer therapy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Fibroblast Growth Factor Receptor (FGFR) alterations drive various cancers.
  • Approved FGFR inhibitors face resistance due to specific mutations.
  • Targeting resistant FGFR mutations is a critical unmet medical need.

Purpose of the Study:

  • To discover and characterize novel macrocycle-based FGFR inhibitors.
  • To evaluate inhibitors against wild-type and resistant FGFR variants.
  • To assess the therapeutic potential of lead compounds in preclinical cancer models.

Main Methods:

  • Synthesis and chemical characterization of macrocycle-based compounds.
  • In vitro enzymatic assays to determine inhibitory concentrations (IC50) against FGFR1/2/3.
  • Cell proliferation assays in FGFR-driven cancer cell lines.
  • In vivo efficacy studies using a bladder cancer xenograft model.

Main Results:

  • A representative compound, 8r, showed potent inhibition of FGFR1/2/3 (IC50: 10.0, 6.9, 30.2 nM).
  • Compound 8r suppressed cancer cell proliferation with low nanomolar IC50 values (2.0-13.3 nM).
  • 8r demonstrated superior activity against resistant FGFR mutations (FGFR1V561M, FGFR2V564F, FGFR2N549K) compared to futibatinib and showed in vivo antitumor efficacy.

Conclusions:

  • Novel macrocycle-based FGFR inhibitors targeting wild-type and resistant variants were developed.
  • Compound 8r is a promising lead candidate for treating FGFR-driven cancers, including resistant forms.
  • This research offers a potential new therapeutic strategy for challenging FGFR-driven malignancies.

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