Chemical Biology / Biophysical Screening PDRA - UOD1742

We are recruiting for an exceptional Chemical Biologist with experience in compound fragment screening / hit identification and chemical biology assay development, to participate in a new academic-industrial global network supported by the Michael J Fox Foundation for Parkinson’s Research. The project aims to: (1) Explore and validate new approaches and novel modalities to target LRRK2; (2) Perform systematic mechanistic, structural and safety analyses to benchmark new inhibitors that emerge from this effort and (3) identify clinically relevant biomarkers for LRRK2 driven Parkinson’s disease that will facilitate the selection of patients who respond to LRRK2 inhibitor therapy. We aim to accelerate the development of Parkinson’s disease therapeutics. There will also be a significant opportunity to collaborate with pharmaceutical companies working in this area.

The appointed researchers will work as part of a newly established “LRRK2-team” that will be based within the state-of-the-art laboratories within the University of Dundee’s Centre for Targeted Protein Degradation, and associated with the research groups of Alessio Ciulli, Will Farnaby and Peter Cossar (CeTPD, www.dundee.ac.uk/cetpd). The mission of this collaboration team will be centred on the design, synthesis, evaluation and optimization of induced-proximity small molecules targeting different regions of LRRK2. These molecules include protein degraders, known as PROTACs and molecular glues, that work by recruiting E3 ligases to induce intracellular ubiquitination and degradation of the target protein; and small molecule inducers/stabilizers of protein-protein interactions. The team will initially focus on three related and synergistic projects: 1) Discovery and optimization of PROTAC degraders of LRRK2, building on the learnings from chemical probe XL-01126 (Liu et al. J. Am. Chem. Soc. 2022); 2) Discovery of LRRK2-kinase targeting glue degraders; 3) Reactivating 14-3-3/LRRK2 binding as a strategy towards small molecule therapeutics.

Your priorities will include:

• Conducting chemical biology-based mechanistic studies on the 14-3-3/LRRK2 protein complex.
• Identifying and validating hit compounds for the 14-3-3/LRRK2 complex using drug discovery screening techniques such as FP, SPR, mass spectrometry, and/or X-ray crystallography.
• Collaborating with other PDRAs in the LRRK2 team to optimize initial hits into molecular glue chemical probes or lead compounds to study the stabilization of the 14-3-3/LRRK2 protein complex.

Who we’re looking for:

• Ph.D. in chemical biology, structural biology, medicinal chemistry, pharmaceutical sciences, or a related field.
• Proven academic and/or industrial track record.
• Excellent interpersonal, communication, and presentation skills.
• Ability to work effectively in a diverse team while also being able to plan and execute work independently.
• Exceptional time management, organizational, and self-motivation skills.
• An open and collaborative approach to scientific work.

The position is available from early October, and for a fixed-term of 2 years. The appointment will be made on University's Grade 7 (Spinal Point 29 -36) (£36,924- £45,163), dependent on experience. For further information about this position please contact, Peter Cossar (PCossar001@dundee.ac.uk), Alessio Ciulli (a.ciulli@dundee.ac.uk) or Will Farnaby (w.farnaby@dundee.ac.uk).

The new Protein Degradation Centre is part of a growing Life Sciences Innovation District, an ecosystem of organisations and people within the life sciences sector in Dundee driving innovation and local economic growth. Opened since January 2023, CeTPD is a first of its kind Centre leading a number of internationally significant projects in the burgeoning new area of translational chemical biology and targeted protein degradation.

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