Poster Presentation 39th Annual Lorne Genome Conference 2018

Targeting telomeric repeat-binding factor 2 (TRF2) with small molecule inhibitors to prevent cancer cell growth (#247)

Alexander P. Sobinoff 1 , Ronnie R. J. Low 2 , David Van Ly 2 , Keriann M. Backus 3 , Anthony J. Cesare 2 , Sandro Cosconati 4 , Hilda A. Pickett 1
  1. Telomere Length Regulation Unit, Children’s Medical Research Institute, University of Sydney, Sydney, NSW, Australia
  2. Genome Integrity Unit, Children’s Medical Research Institute, University of Sydney, Sydney, NSW, Australia
  3. The Skaggs Institute for Chemical Biology and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
  4. DiSTABiF, University of Campania Luigi Vanvitelli, Naples, Italy

Telomeres are specialised DNA-protein structures which cap the ends of chromosomes. Telomeres are bound by the protein complex shelterin, which prevents the aberrant activation of a DNA damage response at chromosome ends. The telomere binding protein TRF2 is a constituent member of the shelterin complex, and is the primary inhibitor of ATM DNA damage signalling at the telomere. Cancer cells have several telomere deficiencies brought about by replication stress, resulting in fragile telomeres and an elevated DDR at the telomere. These deficiencies represent a unique vulnerability which can be exploited for the treatment of cancer. Targeting TRF2, the guardian of the telomere, with small molecule inhibitors which block its ability to protect the telomere represents a unique avenue for the development of targeted cancer therapy. We have synthesised several cell permeable small molecule inhibitors which we have shown directly interact with the TRFH domain of TRF2 in vivo, causing a telomere-specific DNA damage response in cancer cells without affecting mortal controls. This increased DNA damage response coincided with a reduced cell viability specifically in cancer cells. Therefore, cancer cells are potentially more sensitive to the chemical inhibition of TRF2 domains compared to healthy cells, making TRF2 a potentially powerful therapeutic target to kill cancer cells.