Synthesis and testing of novel covalent enzyme inhibitors
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Dr Kurt Lackovic (Co-supervisor) |
Chemical Biology | .(JavaScript must be enabled to view this email address) |
Details of project
The inhibition of enzymes through the covalent binding of an inhibitor to block the active site is gaining increased focus in drug design and the pharmaceutical industry. This project is focussed on the synthesis and testing of a new class of covalent inhibitors and involves a combination of chemical synthesis and assay development and screening.
The compounds to be synthesised contain a reactive ‘warhead’ previously not described in the literature. Synthetic procedures have already been developed and prototype compounds have already been prepared with preliminary data being promising. Further studies are necessary to fully understand the potential of this novel warhead in enzyme inhibitor design.
In tandem, we will develop a screening platform that will allow such novel reactive functionality to be readily identified in a simple high throughput screen. This screening system will also be used to test compound collections considered to contain reactive chemical compounds currently being identified, erroneously, as biologically active compounds. This builds on our published work on pan-assay interference compounds (PAINS) with the aim of developing a simple screening methodology for identifying protein reactive compounds for use in the broader research community.
Research interests
Our research interests are in the design, synthesis and testing of novel chemical compounds with potent biological activity against targets implicated in cancer and other diseases. Such compounds have the potential to be developed as drugs and to help unravel the complex biochemical processes occurring in disease.
We design our drug candidates using a combination of rational drug design principles and careful analysis of structure-activity relationships, whilst ensuring the compounds have appropriate metabolic stability and oral activity (i.e. can be dosed as a pill). The biological testing of the prepared compounds is undertaken in a variety of biochemical and cellular assays, using state-of-the-art screening technologies and data analysis tools available in our lab.
Selected publications
- Baell JB and Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 2010 53 (7): 2719–2740.
Research theme
Cancer
Scientific discipline
- Medicinal Chemistry
Keywords
drug design, synthesis, drug screening, covalent inhibitors, enzyme inhibitors, assay development