Poster Presentation 14th Australian Peptide Conference 2022

Cyclic and stapled peptides for inhibiting the FANCM-RMI interaction at telomeres (#122)

Tianyi Gao 1 , Quynh Ngoc Vu 1 , Haritha Krishna Sudhakar 1 , Toby Passioura 1 , Yu Heng Lau 1
  1. The University of Sydney, Camperdown, NSW, Australia

Telomeres are repetitive nucleoprotein structures that cap the ends of chromosomes. During each cell division, telomeres shorten until they reach a critical length that triggers the DNA damage response, leading to cellular senescence or apoptosis.1 While most cancer cells use the enzyme telomerase to maintain telomere length and acquire immortality, about 5-15% of cancers utilise a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT)1,2. ALT activity is regulated by several proteins including the FANCM-BLM-TOP3A-RMI1-RMI2 complex which acts to limit replication stress, a prominent vulnerability at ALT telomeres. The MM2 domain of FANCM associates with the RMI1/2 subcomplex through a strong hydrophobic interaction3. Disruption of the FANCM-RMI interaction is lethal to ALT-positive cells, providing a possible pathway to treatment for ALT cancers4.

The aim of my project is to develop peptidomimetic inhibitors of FANCM-RMI interactions. In this poster presentation, I will discuss the design of cyclic analogues of the MM2 peptide, including the introduction of non-native amino acids and our progress toward stapling using different chemical linkers. I will also discuss the use of cyclic peptide mRNA display libraries to screen for inhibitors, reporting the results of in vitro binding studies performed on two hits which have shown potent affinity (<30 nM) without further optimisation, and follow-up cellular assays that show disruption of the FANCM-RMI interaction and selective toxicity towards ALT-positive cells.

  1. Okamoto, K.; Seimiya, H. Revisiting Telomere Shortening in Cancer. Cells 2019, 8 (2), 107.
  2. O’Rourke, J. J.; Bythell-Douglas, R.; Dunn, E. A.; Deans, A. J. ALT Control, Delete: FANCM as an Anti-Cancer Target in Alternative Lengthening of Telomeres. Nucleus 2019, 10 (1), 221–230.
  3. Hoadley, K. A.; Xue, Y.; Ling, C.; Takata, M.; Wang, W.; Keck, J. L. Defining the Molecular Interface That Connects the Fanconi Anemia Protein FANCM to the Bloom Syndrome Dissolvasome. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (12), 4437–4442.
  4. Lu, R.; O’Rourke, J. J.; Sobinoff, A. P.; Allen, J. A. M.; Nelson, C. B.; Tomlinson, C. G.; Lee, M.; Reddel, R. R.; Deans, A. J.; Pickett, H. A. The FANCM-BLM-TOP3A-RMI Complex Suppresses Alternative Lengthening of Telomeres (ALT). Nat. Commun. 2019, 10 (1).