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

Lead supervisor: Prof. Matthew Fuchter 

Co-supervisor: Prof. Edward Anderson

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