Potent Cyclic Peptide Inhibitors Disrupt the FANCM–RMI Interaction
FANCM-RMI is a protein-protein interaction that maintains genome stability during DNA repair events in cancers that rely on the Alternative Lengthening of Telomeres (ALT) pathway for survival. We report the first valid chemical inhibitors of the FANCM-RMI interaction discovered by screening cyclic peptides via mRNA display. These inhibitors engage the FANCM-binding pocket of RMI1/2 with nanomolar affinity (<i>K</i><sub>D</sub> = 2-10 nM) and are potent disruptors of the FANCM-RMI interaction (IC<sub>50</sub> = 54-104 nM). X-ray crystallography and alanine scanning reveal novel binding modes and interactions between the cyclic peptides and RMI1/2 that drive high-potency inhibition. Co-immunoprecipitation studies confirm the complete disruption of the native interaction in whole osteosarcoma cell lysates. These inhibitors represent the first validated RMI binders toward developing chemical tools for interrogating the mechanistic roles of FANCM-RMI in mediating genome stability and provide a much-anticipated starting point to accelerate the development of FANCM-RMI inhibitors for intervention against ALT-driven cancers.
Authors
- Quynh Ngoc Vu
- Haritha Krishna Sudhakar
- Tiancheng Huang (ORCID: https://orcid.org/0000-0002-0993-3742)
- Lisa J. Alcock (ORCID: https://orcid.org/0000-0001-9068-0756)
- Lorna Wilkinson‐White (ORCID: https://orcid.org/0000-0002-2385-9358)
- Toby Passioura (ORCID: https://orcid.org/0000-0002-6089-5067)
- Rohan Bythell‐Douglas (ORCID: https://orcid.org/0000-0002-3823-8749)
- Andrew J. Deans (ORCID: https://orcid.org/0000-0002-5271-4422)
- Jixuan Gao (ORCID: https://orcid.org/0000-0002-2209-3143)
- Tianyi Gao (ORCID: https://orcid.org/0000-0001-9689-9118)
- Hilda A. Pickett (ORCID: https://orcid.org/0000-0002-9840-4841)
- Chandrika Deshpande (ORCID: https://orcid.org/0000-0002-5557-519X)
- Reginald Young (ORCID: https://orcid.org/0009-0005-5163-7567)
- Yu Heng Lau (ORCID: https://orcid.org/0000-0001-6560-8410)
Institutions
- The University of Sydney (AU)
- Children's Medical Research Institute (AU)
- ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00365
- Citations
- 4
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Department of Health and Aged Care, Australian Government
- Tour de Cure
- National Health and Medical Research Council