Structural and chemical studies targeting pro-survival Bcl-2 family members — ASN Events
  1. Schedule
  2. Session Five - Poster Session A
  3. Structural and chemical studies targeting pro-survival Bcl-2 family members

Structural and chemical studies targeting pro-survival Bcl-2 family members (#166)

Michael J Roy 1 2 , Amelia Vom 1 , Hong Yang 1 , Brian J Smith 3 , Jonathan B Baell 4 , David C S Huang 1 2 , Peter M Colman 1 2 , Guillaume Lessene 1 2 , Peter E 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
  4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia

Interactions between members of the Bcl-2 family of proteins control the life/death fate of cells by regulating apoptosis. Cancer cells are able to 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 a single agent 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 design strategies at the interface of chemistry and structural biology to target pro-survival members of the Bcl-2 family.
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  2. S.A. Amundson, T.G. Myers, D. Scudiero, S. Kitada, J.C. Reed, and A.J., Fornace, Jr., Cancer Res 60, 6101, (2000).
  3. P.N. Kelly and A. Strasser, Cell Death and Differentiation 18, 1414, (2011).
  4. G. Lessene, P.E. Czabotar and P.M. Colman Nat Rev Drug Discov 7, 989, (2008).
  5. G. Lessene, B.J. Smith, R.W. Gable, and J.B. Baell, J Org Chem 74, 6511, (2009).