AstraZeneca funded PhD studentship: expanding the toolbox of molecular degraders through systematic degron discovery

degraders through systematic degron discovery

Applications are invited for a fully funded, four-year PhD studentship based at the Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID) and the new AstraZeneca Discovery Centre on the Cambridge Biomedical Campus. This is a collaborative project between the laboratories of Dr Richard Timms (University of Cambridge) and Dr Sergio Martínez Cuesta (AZ), and the student will have the opportunity to work across both sites.

Project

Molecular degraders such as PROTACs and molecular glues are exciting new therapeutic modalities which hijack the ubiquitin-proteasome system by recruiting E3 ubiquitin ligases to target proteins, resulting in their ubiquitination and subsequent degradation. However, existing compounds exploit only a handful of the >600 E3 ligases encoded in the human genome: expanding the repertoire of E3 ligases will be critical to improve efficacy, overcome tumour resistance and allow tissue-specific actions.

Towards the goal of enhancing the rational design of novel PROTACs, this project will combine cutting-edge wet-lab and dry-lab techniques to explore the fundamental mechanisms through which E3 ubiquitin ligases target their substrates. The successful candidate will undertake a four-year research project exploiting computational machine learning/AI approaches in concert with wet-lab expression screening and loss-of-function CRISPR screening approaches with the goal of (1) identifying substrates of E3 ubiquitin ligases, (2) delineating the specific molecular features ("degrons") that dictate substrate recognition, and (3) exploring how this knowledge can be exploited to facilitate the rational design of the next generation of molecular degraders. Wet-lab experiments will harness the latest genetic technologies in areas such as CRISPR/Cas9-mediated genome editing, microarray oligonucleotide synthesis, pooled lentiviral library expression screens and next-generation sequencing, while dry-lab work will seek to exploit the dramatic recent advances in the capabilities of machine learning/AI techniques as applied to the prediction of protein structure (e.g. AlphaFold) and protein-protein interactions.

Relevant recent publications include:

Timms RT et al. (2023) Defining E3 ligase-substrate relationships through multiplex CRISPR screening. Nature Cell Biology, in press.

Zhang Z¿Timms RT, Elledge SJ (2023) Elucidation of E3 Ubiquitin Ligase Specificity Through Proteome-wide Degron Mapping. Molecular Cell, in press.

Timms RT and Koren I (2020) Tying up loose ends: the N-degron and C-degron pathways of protein degradation. Biochem Soc Trans, 48 (4): 1557-1567.

Timms et al. (2019) A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science, 365 (6448): eaaw4912.

Koren I, Timms RT et al. (2018) The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell, 173 (7): 1622-1635.

Candidate

We are looking for a highly motivated, enthusiastic and industrious individual who is capable of working both independently and within a team. This studentship would be equally suitable for a student with molecular biology experience who is keen to develop bioinformatics and AI/ML skills, or a student with a background in bioinformatics who is eager to combine computational techniques with experimental work. Thorough training will be provided in both fields and will be adapted depending on the candidate's background. This PhD offers the unique opportunity to work at the interface of basic science and drug discovery in both academic and industry settings, and by the end of the studentship you will have gained a broad range of key experimental, computational and transferable skills that will serve as a springboard for a successful research career.

Applicants should have or should expect to obtain a minimum of a UK 2:1 Honours Degree (or equivalent) in a relevant subject, and should be passionate about discovering new biology with the goal of improving human health.

Environment

Dr Richard Timms is a group leader based in the Cambridge Institute for Therapeutic Immunology and Infections Disease (CITIID) which is situated within the brand-new Jeffrey Cheah Biomedical Centre at the heart of the Cambridge Biomedical Campus. The Timms Lab (https: // www. timmslab.com/) develops and exploits large-scale genetic approaches to study gene function, with a particular focus on how the ubiquitin-proteasome system achieves selective protein degradation. Dr Sergio Martínez Cuesta is an Associate Director in Bioinformatics at AstraZeneca. He leads a group focussed on developing and applying bioinformatic and AI/ML methods to facilitate hit discovery and target identification for new therapeutic modalities.

As a graduate student at the University of Cambridge, you will have access to a wide range of training opportunities and benefit from close supervision provided by a primary and secondary PhD supervisor as well as a personal mentor. You will also become a member of one of the 31 Cambridge Colleges, through which you will have access to accommodation and a wide variety of student clubs, societies and activities.

Funding

The position is fully funded. Beginning on 1st October 2024, you will receive an annual stipend starting at £21,500 and your University tuition fees (at the home rate) will be fully covered for four years. Applications are welcomed from overseas students who are able to cover the additional costs associated with international student fees through scholarships or other funding schemes, such as the Cambridge Commonwealth, European & International Trust (https: // www. cambridgetrust.org/scholarships) or Gates Cambridge (https: // www. gatescambridge.org/); a database of all funding opportunities can be found at https: // www. student-funding.cam.ac.uk/. Further information on how your fee status is determined is available at https: // www. postgraduate.study.cam.ac.uk/finance/fees/what-my-fee-status

Application Process

Interested applicants should apply through the central University of Cambridge Postgraduate Admissions portal (https: // www. postgraduate.study.cam.ac.uk/courses/directory/cvmdpdmed). The closing date for applications is 9th October 2023. During the first stage of the selection process we will consider your academic record, the comments from your referees, and your research experience and achievements to date. We are mindful that the extent of research opportunity varies greatly between candidates and will in many cases have been adversely affected by the COVID-19 pandemic. Candidates may be asked to complete a brief written assessment to establish their suitability for the position, and shortlisted candidates will be invited to attend an interview.

Please direct informal enquiries to Dr Richard Timms ([email protected]) or Dr Sergio Martínez Cuesta ([email protected]) by email.

The University actively supports equality, diversity and inclusion and encourages applications from all sections of society. We place major emphasis on the importance of team work and an enjoyable work environment as a foundation for performing internationally leading research.

English Language: The University requires a high level of proficiency in English. For details, please visit https: // www. postgraduate.study.cam.ac.uk/courses/directory/blbcpdpbc/requirements

The University has a responsibility to ensure that all employees are eligible to live and work in the UK.

Department of Medicine

RC38327

Studentships

5 September 2023

9 October 2023