The design of chemical inhibitors to disrupt protein-protein interactions (PPI) is a challenging task in drug discovery. Thus, while key proteins that mediate disease-associated pathways such as gene expression, telomere maintenance, and DNA repair are tantalising targets for drug discovery, they are often overlooked in the drug discovery process.
One such mechanism, the Alternative Lengthening of Telomeres (ALT), exploits DNA repair proteins to extend its telomeres as a way to evade programmed cell death and achieve continued cell growth. Disruption of a key PPI called FANCM-RMI is selectively toxic to ALT-positive cancer cells providing an attractive therapeutic window for targeting. However, despite this, no ALT-targeting therapies are currently available in the clinic.
In this presentation, I will discuss using peptide phage display for the discovery of inhibitors targeting FANCM-RMI. Using a multi-pronged chemical approach to inhibitor discovery we have shown that selectively disrupting FANCM-RMI within the ALT mechanism could be a viable therapy for cancers that rely on ALT such as osteosarcomas, with these methods generally applicable to other challenging PPI drug targets.