Apoptotic resistance is a hallmark of cancer cells, and resistance to apoptosis is a major barrier to the efficacy of chemotherapeutic drugs. Paradoxically, chemotherapeutic/radiation therapies are aimed at inducing apoptosis in cells that have intrinsic resistance. Commitment to apoptosis and regulation of the cell life-death switch is dependent largely on protein-protein interactions and the formation of multi-protein complexes, yet the regulation of these complexes is still not fully elucidated.
One crucial member of the apoptosis machinery is BAK. Once activated, BAK permeabilises the mitochondrial membrane, releasing factors which commit a cell to death. BH3 mimetics have been developed, which inhibit anti-apoptotic BCL-2 proteins allowing activation of BAK and BAX. Some of these agents now have FDA approval, but they have on-target toxicity resulting in severe limitations to their use in clinical settings.
The unmet need is still for a drug that promotes apoptosis in cancer cells, without significant side effects.
In ground-breaking work, we identified the first and obligatory step in BAK activation, which is regulated by tyrosine kinase BMX. BMX phosphorylates BAK on residue Y108, and locks BAK in an inactive conformation making it insensitive to activators, blocking apoptosis. Removal of BMX protein via RNA interference has been shown to sensitize cells to apoptotic cell death.
Our therapeutic hypothesis therefore is that removal of BMX will reverse the apoptotic block observed in resistance cells and result in increased levels of de-phosphorylated BAK, re-sensitising cells to a wide range of chemotherapeutic drugs, radiation therapies and other existing cancer treatments. This innovative approach will enable a therapeutic window to be created, which can be exploited to increase cell killing with reduced doses of current therapies. Not only making these existing agents more efficacious, but has the potential to reduce side effects and increase quality of life during therapy.
PROteolysis Targeting Chimeras (PROTACs) regulate protein function by degrading target proteins instead of inhibiting them. The removal of the protein via proteolysis can have many advantages over small molecule inhibition, such as enhanced selectivity for the target protein. This project will used a structure-guided approach to design, synthesis and test PROTACs against BMX to potentiate apoptotic cell death in cancer cells.
AIM 1: Utilise structural biology techniques including X-ray crystallography and NMR to determine the structure of tyrosine kinase BMX and use this and previously determined structures of individual domains of BMX to design and synthesise PROTAC molecules.
AIM2: Characterise binding of the PROTAC molecules to BMX both in vitro using structural techniques (x-ray crystallography and NMR) and biophysical methods to detect and analysed binding to recombinant proteins.
AIM3: Characterise the PROTAC molecules in cell-based models. Initially the molecules will be characterised in paired cell line model +/- BMX overexpression to determine the effect on cell growth, sensitivity to induction of apoptotic cell death and cellular morphology. These studies would then be extended to a panel of normal and cancer prostate cell lines to determine if a therapeutic window can be developed in these cell lines with the combination of PROTAC molecules in combination with chemotherapeutics routinely used to treat prostate cancer.
Entry requirements:
- Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
- Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
- Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
- Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
- Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above.
For further information please contact [Email Address Removed]
Application advice:
To apply please refer the application instructions at
https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
You will need to apply for the PhD place at University of Leicester and also submit your online application notification to MIBTP. Links for both are on the above web page.
Project / Funding Enquiries: For further information please contact [Email Address Removed]
Application enquiries to [Email Address Removed]
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