The discovery of robust septin binders to validate their potential as a future drug target

Commercial partner: Jazz Pharmaceuticals 

Septins are filamentous GTPases that associate with cell membranes and the cytoskeleton (actin, microtubules), and play essential roles in cell division and cellular morphogenesis. Septins are implicated in many human diseases including cancer (Nature 615, 517–525 (2023)), infection (Nat. Commun.15, 4104 (2024)) and neurodegenerative conditions, such as Alzheimer’s disease (Science 384, eadd6260 (2024)). In principle, high quality small molecules that reversibly perturb septin organization and function would be valuable tools for dissecting septin biology and could be used for the therapeutic treatment of septin-related diseases. However, such chemical tools are lacking, with the major molecule used currently – forchlorfenuron – being non-selective and non-specifically cytotoxic.

Building on the recent discovery of a more robust septin binder (ReS19-T) (Science 384, eadd6260 (2024), this project will further explore the potential to develop more potent and selective septin binders with robust and well-understood mechanisms of action. Computational and experimental medicinal chemistry will be used to design, synthesis and study new septin binders, that will be characterized in a suite of downstream assays. These will include effects of the newly designed molecules on septin (dis)assembly in vitro using purified proteins, as well as study in cellular and zebrafish models. This cuts across several remits of the MRC, including precision medicine, translation skills and interdisciplinary skills.

The project will be led by Prof. Matthew Fuchter, who is an experienced medicinal chemist who has recently moved to Oxford. Prior to that he was a Professor of Chemistry at Imperial College London and Director of the Imperial College Centre for Drug Discovery Science. The project will be in close collaboration with Prof. Serge Mostowy (London School of Hygiene and Tropical Medicine), who is an expert in septin biology and has many established assays and models to study septin binders. The project will be in partnership with Jazz Pharmaceuticals. It represents a new collaborative project for the team and a new interaction with Jazz Pharmaceuticals, which, in addition to novel science, may form the basis of further growth and partnerships in the future.

Apply using course: DPhil in Chemistry

MRC INDUSTRIAL CASE STUDENTSHIPS 2025

Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.

ELIGIBILITY

They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.

FUNDING PACKAGE

Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.

APPLICATIONS DEADLINE

Applications must be received by 12 noon (UK time) Tuesday 3 December 2024. Details on entry requirements and how to apply can be found below.

For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.

HOW TO APPLY

Before applying for this project we recommend you contact the lead supervisors for informal discussion.

To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.

If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.

If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email mrc@medsci.ox.ac.uk.