Design and structural characterisation of Bcl-2 inhibitors
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Dr Peter Czabotar (Co-supervisor) |
Structural Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Previous work in the Structural Biology and Chemical Biology divisions has produced compounds mimicking alpha helical BH3-peptides. Small molecules binding to Bcl-xL with low micromolar binding affinities have been obtained along with their X-ray structures in complex with Bcl-xL.
This project will be divided between the chemistry laboratory (preparation of analogues using structure-guided design), the screening facility (assessment of binding affinity) and the Structural Biology division to obtain structural information on their binding mode. The work will involve learning the chemistry required to prepare these compounds, purification and analysis techniques. The student will then use X-ray crystallography to determine the structure of these compounds in complex with Bcl-XL. Target compounds will be defined by using the structural information and the known structural-activity relationship of this family of molecules.
Potent molecules obtained will then be used in cellular experiments to verify their mode of action and to elucidate the role of the pro-survival proteins in cancer development.
Project references
- Lessene G, Czabotar P & Colman P. BCL-2 family antagonists for cancer therapy. Nature Reviews Drug Discovery. 2008 7(12):989-1000.
- Lessene G, Smith BJ, Gable RW Baell JB. Characterization of the two fundamental conformations of benzoylureas and elucidation of the factors that facilitate their conformational interchange, Journal of Organic Chemistry. 74:6511-6525.
Research interests
Interactions between members of the Bcl-2 family of proteins control the life/death fate of cells through the regulation of apoptosis. Cancer cells are able to evade apoptosis through over expression of pro-survival members of the Bcl-2 family such as the protein Bcl-xL. 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 chemotherapies.
We are interested in designing compounds that reproduce the interactions that occur between pro-survival proteins and pro-apoptotic proteins. Such compounds would nullify pro-survival activity and would thus hold promise as potential cancer therapeutics.
Research theme
Cancer
Scientific discipline
- Cell Biology
- Chemistry
- Medicinal Chemistry
- Structural Biology
Keywords
Apoptosis, structure-guided medicinal chemistry, cell biology