Targeted protein degradation using small molecule as a general approach to probe biology

Project Description

Medical Research Scotland
PhD Studentship Award

This project is one of 13 four year PhD Studentships funded by Medical Research Scotland (http://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and Company. The Studentship will provide the first-class academic and commercial training needed to equip the successful candidate for a science career in an increasingly competitive market.

"Novel PROTAC-based chemical biology approaches to induced protein knockdown across the proteome" to be delivered by the University of Dundee [Supervisors: Professor Alessio Ciulli (Biological Chemistry and Dug Discovery) Dr Gopal Sapkota and Professor Dario Alessi (both MRC Protein Phosphorylation and Ubiquitylation Unit)] and Boehringer Ingelheim Regional Centre Vienna GmbH & Co KG (www.boehringer-ingelheim.com/) [Company supervisor: Dr Darryl McConnell].

Abnormal behaviour of proteins can alter cellular function, often resulting in disease. To validate protein targets for drug discovery programmes, typical approaches involve constitutive knockout or transient knockdown of target genes. These approaches, however, suffer from several limitations. For example, gene knockout is irreversible and often not viable, while gene knockdown such as RNA interference requires long treatments, is often incomplete, and can lead to undesired off-target effects. These shortcomings motivate the need for new approaches to intervene directly on proteins, i.e. at the post-translational level.

Inducing protein degradation is an approach now made possible by the relatively recent development of an exciting new class of chemicals, called PROteolysis TArgeting Chimeras (PROTACs). PROTACs are bivalent molecules that are composed conceptually of two ligands: one ligand binds to a target protein of interest, while the second ligand engages an E3 ubiquitin ligase – a class of enzymes naturally involved in tagging substrate proteins as a natural mechanism to induce their degradation. PROTACs are emerging as an attractive modality of chemical intervention, defined by a catalytic rather than occupancy-based mode of action, and a prolonged duration of action. Importantly, PROTACs can mediate rapid and potent degradation of a target protein in a highly selective fashion over the thousands of proteins across the proteome. However, this approach does not currently allow us to target proteins which do not have suitable small-molecule ligands that bind to them.

In this project, you will develop and apply a general strategy for targeted knock-down of any protein inside cells, combining latest technologies for targeted protein degradation (PROTACs) and genome engineering (CRISPR). The project will combine the expertise of the Ciulli Lab in targeted protein degradation, with the expertise of the Sapkota and Alessi Labs in cell signalling pathways. The project is in collaboration with Boehringer Ingelheim, which will bring expertise in a wide range of drug discovery areas relevant to the collaboration, from disease biology to drug discovery. Boehringer Ingelheim can also offer a training period in it’s state of the art cancer research facilities in Vienna, Austria for the successful student.

The tools generated by the project will enable studying the biological function of interesting proteins, and their role in disease. Successful development of this approach will potentially open up many new areas of disease biology research and unlock therapeutic strategies against a whole range of human proteins in an equally diverse range of human diseases.

ENQUIRIES:

Enquiries should be sent by email to Ms Lesley Coats:
[Email Address Removed]

APPLICATIONS:

Candidates must have obtained, or expect to obtain, a minimum 2.1 undergraduate degree and preferably also a Masters, or equivalent for degrees obtained outside the UK, in Chemistry, Biochemistry, Chemical Biology, Structural Biology or a related discipline. Applications from candidates with either a strong chemical or biological science background are encouraged, where the applicant is interested in learning the other discipline.

Candidates must submit their application online through the application form available at:
http://www.lifesci.dundee.ac.uk/apply-now
Your application should include a full Curriculum Vitae, the contact details of 2 academic references (including email addresses) and a covering letter, explaining why you wish to carry out this project.

Interviews are expected to take place approximately 3-4 weeks after the closing date for applications.

It is anticipated that the PhD Studentship will start in September 2018.