Supervised by Dr David Mann (Department of Life Sciences, Imperial College London) and Professor Alan Armstrong (Department of Chemistry, Imperial College London)

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 d.mann@imperial.ac.uk by 29^th November 2019.

Informal enquiries are welcomed and should be sent to Dr David Mann d.mann@imperial.ac.uk or Professor Alan Armstrong a.armstrong@imperial.ac.uk.

Student eligibility:

The studentship is funded by Sarcoma UK and includes 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. 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 1^st February 2020.

 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.

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.

In the group of Dr Jie Song, at the Department of Life Sciences, Imperial College London

Address: South Kensington Campus, London SW7 2AZ, UK

This PhD project aims to characterise Polycomb-based epigenetic regulation in the model plant Arabidopsis. Throughout development, Polycomb silencing acts in a strictly controlled manner, spatially –with confined regions being silenced, and temporally –target loci being silenced in specific periods in the life cycle. The PhD student will investigate how the chromatin modifying complex Polycomb is targeted to specific loci in order to give rise to such distinct gene silencing patterns.

Informal inquiries are welcome and should be sent to Dr Song (j.song@imperial.ac.uk).

How to apply:

Please email Dr Song (j.song@imperial.ac.uk) and include in your application:

• A cover letter
• Your CV 
• Your transcripts
• Three references sent directly from the referees

Applications will be considered as they are received and the position will remain open until filled.  

General entry requirements for graduate studies at Imperial College London can be found at http://www.imperial.ac.uk/study/pg/apply/requirements/.

 Funding notes:

This is a 4-year PhD Studentship, including home fees and a standard stipend of £17,009, funded jointly by the Royal Society and the Department of Life Sciences, Imperial College London.

International applicants: please note that the fees paid are at UK/EU level. Any shortage in fees will need to be met by the applicant from external sources.