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Updated: Sep 19, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Potent Cyclic Peptide Inhibitors Disrupt the FANCM-RMI Interaction

Lisa J Alcock1, Tianyi Gao1, Rohan Bythell-Douglas2

  • 1School of Chemistry, The University of Sydney, Camperdown, NSW 2145, Australia.

Journal of Medicinal Chemistry
|June 6, 2025
PubMed

Insights

Researchers discovered the first chemical inhibitors targeting the FANCM-RMI protein interaction, crucial for genome stability in Alternative Lengthening of Telomeres (ALT) pathway cancers. These potent cyclic peptide inhibitors offer a new avenue for cancer therapy development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The FANCM-RMI protein-protein interaction is vital for maintaining genome stability.
  • This interaction is critical in cancers utilizing the Alternative Lengthening of Telomeres (ALT) pathway for survival.

Purpose of the Study:

  • To identify and characterize the first chemical inhibitors of the FANCM-RMI interaction.
  • To explore the potential of these inhibitors for developing new cancer therapies.

Main Methods:

  • Screening of cyclic peptides using mRNA display to identify inhibitors.
  • Characterization of inhibitor binding affinity (KD) and disruptive potency (IC50).
  • X-ray crystallography, alanine scanning, and co-immunoprecipitation studies to elucidate binding modes and in-cell activity.

Main Results:

  • Discovery of potent cyclic peptide inhibitors engaging the RMI1/2 binding pocket with nanomolar affinity (KD = 2-10 nM).
  • Inhibitors demonstrated significant disruption of the FANCM-RMI interaction (IC50 = 54-104 nM).
  • Structural studies revealed novel binding modes, and cell-based assays confirmed disruption of the native interaction.

Conclusions:

  • These cyclic peptides are the first validated inhibitors of the FANCM-RMI interaction.
  • They serve as valuable chemical tools for studying genome stability mechanisms.
  • They represent a promising starting point for developing therapeutics against ALT-driven cancers.

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