2. Academic Validation
  3. Cell-Active Peptide Inhibitors of the FANCM-RMI Interaction

Cell-Active Peptide Inhibitors of the FANCM-RMI Interaction

  • J Med Chem. 2025 Nov 27;68(22):24672-24683. doi: 10.1021/acs.jmedchem.5c02655.
Lisa J Alcock 1 2,  Joshua Mills 1,  Rohan Bythell-Douglas 3,  Haritha Krishna Sudhakar 1,  Chandrika Deshpande 4,  Toby Passioura 4,  Andrew J Deans 3,  Yu Heng Lau 1 5
Affiliations

Affiliations

  • 1 School of Chemistry, The University of Sydney, Camperdown, New South Wales 2006, Australia.
  • 2 School of Molecular and Life Sciences, Curtin University, Bentley, Western Australia 6102, Australia.
  • 3 Genome Stability Unit, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
  • 4 Sydney Analytical Core Research Facility, The University of Sydney, Camperdown, New South Wales 2006, Australia.
  • 5 ARC Centre for Innovations in Peptide and Protein Science, The University of Sydney, Camperdown, New South Wales 2006, Australia.
PMID: 41236382 DOI: 10.1021/acs.jmedchem.5c02655
Abstract

The FANCM-RMI protein-protein interaction plays an essential role in cancers that extend their telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. Here, we report the first cell-active peptide inhibitors of FANCM-RMI. Screening of mRNA-displayed peptide libraries treated with trans-1,4-dibromo-2-butene led to the discovery of both linear and cyclic peptide hits that bind RMI at the FANCM interaction site. The most potent peptides engage RMI with nanomolar affinity (KD = 4-31 nM) and outcompete the native peptide mimic of FANCM (IC50 = 24-155 nM). A bound X-ray crystal structure of the top hit revealed novel interactions at the RMI binding site that were not found in the native interaction. Conjugation to a cell-penetrating peptide resulted in inhibitors that induced an antiproliferative effect in ALT-positive osteosarcoma cell lines. These inhibitors represent the first bioactive RMI Binders that can be used as chemical tools for studying the involvement of FANCM-RMI in ALT-driven cancers.

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