Poster Presentation Melbourne Protein Group Student Symposium 2013

Structural and chemical studies targeting pro-survival Bcl-2 family members (#69)

Michael Roy 1 2 , Amelia Vom 1 2 , Soo San Wan 1 , Hong Yang 1 , Brian Smith 3 , Peter Colman 1 2 , Guillaume Lessene 1 2 , Peter Czabotar 1 2
  1. Walter & Eliza Hall Institute , Parkville, VIC, Australia
  2. Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria, Australia

Interactions between members of the Bcl-2 family of proteins control the life/death fate of cells by regulating apoptosis. Cancer cells can evade apoptosis through over-expression of pro-survival members of the Bcl-2 family, such as the proteins Bcl‑xL and Mcl‑1. This is not only an important step in the progression to cancer but also a mechanism through which cancer cells can become resistant to standard anti-cancer therapies 123.

Small molecules able to mimic the activity of pro-apoptotic BH3-only proteins hold potential for reactivating apoptosis in tumours; either as single agents in certain tumours, or to sensitise cancers to existing therapies 4 .  Previous work at WEHI has led to the development of small molecules possessing a benzoylurea core which are able to mimic alpha-helical BH3 peptides and which bind to Bcl-xL with low micromolar binding affinity 5 . Co-crystal structures for a number of these compounds in complex with Bcl-xL have been obtained and have formed the basis for further structure-based optimization.

This poster will outline new developments in our lab using structure-based approaches to target pro-survival members of the Bcl-2 family.

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