Elaboration of benzoylurea inhibitors targeting pro‑survival Bcl‑x<sub>L</sub> — ASN Events
  1. Schedule
  2. Session 10: Poster Session C
  3. Elaboration of benzoylurea inhibitors targeting pro‑survival Bcl‑xL

Elaboration of benzoylurea inhibitors targeting pro‑survival Bcl‑xL (#357)

Michael Roy 1 2 , Amelia Vom 1 , 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 1, 2, 3 . 

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, in particular Bcl-xL.

  1. J.M. Adams and S. Cory, Oncogene 26, 1324, (2007).
  2. S.A. Amundson et al., 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 et al., J Org Chem 74, 6511, (2009).