Poster Presentation 14th Australian Peptide Conference 2022

Chemical inhibitors of telomeric PPIs in ALT positive cancers (#209)

Haritha Krishna Sudhakar 1 , Tianyi Gao 1 , Tiancheng Huang 1 , Lorna Wilkinson-White 1 , Yu Heng Lau 1
  1. University of Sydney, Sydney, NSW, Australia

Malignantly transformed cells are those that have attained immortalisation by overcoming the inherent telomere loss that occurs with each cell division1. These cells, often cancerous, depend on either telomerase or Alternative Lengthening of telomeres (ALT) pathway for their survival2,3, with  ALT-positive cancers having an increased incidence of patient death making this pathway an attractive therapeutic target4. This project targets the FANCM-BTR complex, a key protein-protein interaction (PPI) involved in resolving stalled replication forks which is co-opted by ALT cancers to suppress genome instability and maintain cells in a viable state5. Recently, it has been shown that the interruption of FANCM-BTR is selectively cytotoxic to ALT cancer cells6. Given the novelty of this discovery, there are currently no robust inhibitors with sufficient potency and specificity aimed at this PPI.

In this presentation, I will discuss the progress made towards developing chemical inhibitors that disrupt FANCM-BTR formation in ALT-positive cancers. PPI surfaces include specific regions, termed ‘hot spots’, comprising of a subset of residues contributing to majority of binding.  NMR-fragment based screening has revealed small molecule hits capable of binding to these hot spots in the FANCM-BTR complex which were validated using SPR. Extensive SAR on initial fragment hits is underway to identify optimal binding moieties contributing towards a fragment-directed peptide screen. Orthogonally, using structure-based rational design based on peptidomimetic modifications on the BTR binding domain of FANCM, we are developing bi-cyclic peptides tethered to strategically placed trivalent-linker that constrain the peptide backbone into the binding conformation. Designed peptides will be screened using biophysical assays such as FP and SPR and, coupled with the fragment moieties, a library of fragment-peptide hybrid inhibitors will be produced biological evaluation.   

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