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Covalent Inhibition of the Anti-Apoptotic Protein Mcl1 as a Route to Therapy in Sarcoma


Project Description

Resistance to apoptosis is a common feature of cancer, often achieved through over-expression of anti-apoptotic proteins of the Bcl-2 family [Hata et al 2015]. Bcl-2 family members function by protein-protein interactions to sequester pro-apoptotic proteins such as Bim and Noxa preventing their oligomerisation and pore formation in the outer mitochondrial membrane, repressing cytochrome c release and hence blocking commitment to programmed cell death. Many studies have demonstrated that cancer cells can be selectively killed by compromising the function of Bcl-2 family members (reviewed in [Hata et al 2015]).

Mcl-1 is a Bcl-2 family member that is among the most commonly upregulated genes in human cancer and impairment of Mcl-1 function enhances sensitivity to induction of apoptosis. We have applied our covalent drug screening methodology [Craven et al 2018] to identify potential inhibitors of Mcl1 and this project will biochemically and structurally characterize the hits and chemically develop them into more potent and selective agents for Mcl1 inhibition in sarcoma. This drug development PhD will involve a variety of techniques all established in the host labs: ligand-protein structural and biophysical analyses, medicinal chemistry, protein expression and purification, mass spectrometry and proteomics and testing compounds in biological systems.

This is an interdisciplinary project that will involve a mix of biochemistry and chemistry and will suit an individual with the aptitude and desire to cross traditional scientific boundaries.

How to apply

Please send your CV, a one page cover letter explaining why you are suitable for the studentship and for this project, and the names and e-mail addresses of two referees to Dr David Mann by 29th November 2019.

Informal enquiries are welcomed and should be sent to Dr David Mann or Professor Alan Armstrong .

Student eligibility

The studentship is funded by Sarcoma UK (https://sarcoma.org.uk/). Applicants should have, or be about to obtain, a Masters qualification and a 2.1 or higher undergraduate degree in Chemistry, Biochemistry or similar. Exceptional students at Bachelors level without a Masters will also be considered. The project will start on 1st February 2020.

Funding Notes

A stipend for 3.5 years at current research council rates of £17,009 per year tax free and covers tuition fees for UK or EU citizens only.

References

Craven, G.B., Affron, D.P., Allen, C.E., Matthies, S., Greener, J.G., Morgan, R.M.L., Tate, E.W., Armstrong, A. & Mann, D.J. (2018) Agnew Chem, 57, 5257-61: High-throughput kinetic analysis for target-directed covalent ligand discovery (https://www.ncbi.nlm.nih.gov/pubmed/29480525)

Hata AN, Engelman JA, Faber AC. (2015) Cancer Discov. 5, 475-87. The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics (https://www.ncbi.nlm.nih.gov/pubmed/25895919)

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