Medicinal Chemistry/Organic Chemistry - PDRA - UOD1738

We are recruiting for an exceptional Medicinal Organic Chemist with experience in drug design/synthesis and lead optimisation to advance compounds with appropriate pharmaceutical properties 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 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:

• Design, synthesize and purify compounds, and to contribute to the lead optimisation of advanced hit compounds by enhancing potency in synergy with appropriate pharmaceutical properties of compounds.
• Drive the optimization of known degraders and hit compounds with activity in cells, in the first instance for our most advanced PROTAC series, into compounds that will be appropriate for working in vivo, are orally bioavailable and ultimately active in the brain.

Who we’re looking for:

• A Ph.D. in organic chemistry, medicinal chemistry, drug discovery, pharmaceutical sciences, or a related discipline
• High-level of expertise in synthetic organic chemistry and synthetic route design is essential.
• Experience in multi-step organic synthesis, small molecule characterisation via MS and NMR and state-of-the-art chromatography purification techniques.
• Excellent interpersonal, communication and presentation skills.
• Capable of working in a diverse team, but able to plan and work independently.
• Exceptional time management, organisational and self-motivational skills.
• An open and collaborative approach to science.
• Experience with structure-based drug design and studying protein-ligand interactions.
• Experience with the development of PROTACs and/or molecular glue degraders
• Understanding of pharmacology, metabolism and pharmacokinetics and other medicinal chemistry principles necessary for lead optimisation processes.
• Interest in understanding pathways that are linked to neurodegeneration and Parkinson’s disease and how research in this area can be exploited to accelerate drug discovery.

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 Will Farnaby (w.farnaby@dundee.ac.uk), Alessio Ciulli (a.ciulli@dundee.ac.uk) or Peter Cossar (PCossar001@dundee.ac.uk).

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