Poster Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Chemical inhibitors of telomeric PPIs in ALT positive cancers (#218)

Haritha Krishna Sudhakar 1 , Lorna Wilkinson-White 2 , Tianyi Gao 1 , Quynh Vu 1 , Yu Heng Lau 1
  1. School of Chemistry, The University of Sydney, Sydney, NSW, Australia
  2. Sydney Analytical, THE UNIVERSITY OF SYDNEY, Sydney, NSW, Australia

Telomeres are repetitive sequences of non-coding nucleoprotein structures that cap chromosomal ends preventing degradation1. Malignantly transformed cells are those that have attained immortalisation by overcoming the inherent telomere loss that occurs with each cell division2. These cells, often cancerous, depend on either the telomerase enzyme or Alternative Lengthening of telomeres (ALT) for their survival3,4. Cancers that predominantly utilise ALT are characterised as refractory to treatment with an increased incidence of patient death making this pathway an attractive therapeutic target5,6.

This project targets the FANCM-BTR complex, a key protein-protein interaction (PPI) involved in resolving stalled replication forks that frequently occur at telomeric DNA. It is co-opted by ALT cancers to suppress genome instability and maintain cells in a viable state7. Recently, it has been shown that the interruption of FANCM-BTR is selectively cytotoxic to ALT cancer cells8. Given the novelty of this discovery, there are currently no robust chemical inhibitors with sufficient potency and specificity to target this interaction. In this presentation, I will discuss the progress made towards developing peptide and fragment inhibitors that disrupt FANCM-BTR formation in ALT-positive cancer.

Targeting PPIs has been an inherent challenge in the field of drug discovery. This target class possesses a relatively large, seemingly flat interaction surface that is regarded as undruggable using traditional small-molecule methods9. PPI surfaces are now recognized to include specific regions, termed ‘hot spots’, comprising of a subset of residues that contribute to the majority of binding10.  Using a multi-pronged approach, our group has found small molecule “hits” capable of binding to these “hot spot” regions in the FANCM-BTR complex using Fragment-Based Drug Discovery, and these hits have been validated using surface plasmon resonance. Additionally, through the use of Rational Drug Design, we are developing bi-cyclic peptides that mimic the BTR binding domain of FANCM.

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