Telomeres are repeating nucleoprotein structures located at the ends of chromosomes, which are crucial for regulating cell proliferation and maintaining genomic integrity. Telomeres shorten after each cell division and thus limit cell replication once a critically short length is reached.

For cancer cells to overcome replicative mortality, 10-15% of cancers extend their telomeres using a cellular mechanism known as Alternative Lengthening of Telomeres (ALT). To date, there are no clinical therapies that target ALT, hence, inhibitors of the ALT pathway represent an unexplored avenue for cancer treatment.

The ALT mechanism is mediated by the protein-protein interaction between FANCM and RMI, representing a genetically validated target for inhibiting ALT activity.¹ There are currently no known inhibitors of FANCM-RMI interaction.² FANCM interacts with RMI via a well-defined MM2 peptide domain, providing an opportunity for novel peptide-based inhibitor development.³

We used phage display to discover novel and potent cyclic peptide inhibitors of the FANCM-RMI interaction. Using dibromoxylene with 1,3- and 1,4-substitution patterns as staple linkers, we obtained enriched peptide sequences with strong consensus towards sequences that closely resembled the native MM2 peptide. We synthesized six cyclic peptide candidates and assessed their binding affinity for RMI in a competitive fluorescence polarisation assay (IC₅₀ = 0.4-2.5 μM). With further optimisation of their drug-like properties, particularly solubility and cell-penetrating capability, these peptides will serve as design templates for the development of novel inhibitors to target ALT-positive cancers.