In 10-15% of all cancers, unlimited cell replication is enabled by a process known as the Alternative Lengthening of Telomeres (ALT). The ALT mechanism involves dysregulation of the Fanconi Anemia and Bloom’s protein complexes that have translocase and helicase activity respectively, working in tandem to mediate homology-directed extension at telomeric replication forks. Genetic studies have shown that the FANCM-RMI interaction is a key protein-protein interaction target in the ALT pathway that selectively causes lethality upon inhibition in ALT-positive cancer cells.
I will present our progress towards screening various cyclic peptide display libraries to develop the first chemical inhibitors of the FANCM-RMI interaction. Using the flexizyme-based RaPID approach for incorporating cyclisation motifs during mRNA display, we have discovered several cyclic peptide inhibitors that have low-nanomolar affinities for RMI and can displace FANCM in competitive assays. We have also used CLIPS linkers for cyclising peptides during phage display to discover smaller sized inhibitors with mid-nanomolar affinities. Interestingly, a comparison of enriched sequences and bound crystal structures reveals systematic differences in the outcomes of the two peptide screening approaches.