Current Research. Examples of current research projects:

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1 Current Research Dr Richard Foster Medicinal Chemistry and Chemical Biology Group Leader Medicinal Chemistry Tutor School of Chemistry University of Leeds +44 (0) Our group is interested in the design, synthesis and optimisation of small molecules for therapeutic application or their use in the elucidation of biological function. By combining tools and techniques in medicinal chemistry, computer-aided drug design and chemical genetics we aim to identify and optimise targeted small molecules as key modulators of specific biological function to support both basic target validation and as potential starting points for future drug discovery. These multidisciplinary projects form part of collaborative frameworks with scientists and clinicians from a variety of backgrounds. We are always interested in initiating new collaborations with groups who share a common interest in developing innovative strategies to treat or to detect disease. Often pump-priming resources can be provided by my group in order to facilitate the generation of proof of principle data for the project. Please click here for further details. Examples of current research projects: Small molecule therapeutics: Various projects are underway to identify and optimise small molecule modulators of biological targets from a variety of target classes and therapeutic areas to support basic target validation (pharmacological tool compounds) and as potential starting points for future drug discovery (hits and leads). Case studies: Development of a novel anticoagulant with minimal bleeding risk We have identified potent, novel small molecule inhibitors of a key enzyme involved in regulation of the coagulation cascade with exceptional in vivo efficacy. The inhibitors have been identified by a number of parallel approaches incorporating virtual drug design, chemical synthesis and HTS of large drug-like small molecule libraries. Presently, we are optimising the inhibitors for target potency, specificity and drug-like physicochemical properties using iterative rounds of medicinal chemistry development and screening using a panel of orthogonal bioassays. Collaborators: Helen Philippou, Robert Ariens, Colin Fishwick Identification of novel inhibitors of TRP ion channel function as potential therapeutics We have identified a series of novel inhibitors of a TRP ion channel implicated in cardioprotection. The compounds have been developed as agents to support detailed understanding of the role of the protein target and its relevance in disease as well for future development of small molecule-based therapeutics. These dual aims are being achieved through iterations of directed chemical synthesis aided by pharmacophore-based design and screening via a panel of orthogonal assays. Collaborators: Lin-Hua Jiang, David Beech, Rao Sivaprasadarao

2 Diagnostics We are working on several projects to identify chemical probes as diagnostics to monitor and modulate biological mechanisms, including the design of targeted contrast imaging agents for MRI and labeled probes to understand the complex signaling networks in disease pathways as well as targeted biosensors for possible point-of-care healthcare applications. Targeted contrast agents We are designing and synthesising modular targeted high relaxivity MRI contrast agents for protein targeted cardiovascular disease monitoring and prevention. Collaborators: Robin Bon, Stephen Gilbert, Sven Plein, Azhar Maqbool Electrochemical microarrays We are developing a small molecule electrochemical microarray for detection of protein-small molecule binding interactions. We are designing multiplexed small molecule microarrays to detect binding of proteins by electrochemical impedance. This approach constitutes a highly promising and flexible method towards the label-free detection of small molecule-protein interactions and has a number of potential therapeutic and translational applications, including micro- HTS and point-of-care diagnostics. Collaborator: Stephen Johnson Facilities Our laboratories are superbly equipped for research at the interface between chemistry and biology. We recently moved into newly refurbished laboratories in the School of Chemistry, which provide 2m fume cupboards for each researcher. We are located close to facilities for analytical and preparative HPLC, semi-preparative mass-directed HPLC, analytical LC- MS, automated flash chromatography, IR, NMR (up to 500 MHz), automated synthesis, protein expression, highthroughput screening and computational molecular modelling and drug design. Funding Current research has been funded by the BHRC (Leeds), MRC, Parkinson s UK, BHF, AICR, BBSRC and CRUK.

3 Current group members: Post-doctoral research associates Dr Jeff Plante Jeff is working on a number of projects directed at the generation of chemical tools as diagnostic agents, including the design of novel contrast imaging agents targeting proteins causative in the onset of cardiovascular disease as well as the design of electrochemical impedance-based microarrays for potential point-of-care healthcare applications. Jeff obtained his PhD from Penn State University and joined the group following a post-doctoral position with Andy Wilson (Leeds). Dr Ian Yule Ian is working on a MRC funded project to identify small molecule inhibitors of a protease involved in blood coagulation as possible therapeutics to treat thrombosis. Ian joined the group following a PhD in medicinal chemistry (Fishwick, Leeds), industrial experience at Vernalis and a chemistry degree from the University of Leicester. Dr Charlotte Revill Charlotte joined the group from the Dundee Drug Discovery unit following a PhD in medicinal chemistry at Newcastle University and a MChem from the same University. Charlotte is working on a MRC funded project to identify small molecule inhibitors of a specific protease involved in blood coagulation as possible therapeutics to treat thrombosis. Dr Rachel Trowbridge Rachel is working on a number of high-throughput assay transfer and screening projects directed at biological targets of interest to the group. Rachel has industrial experience in the biotech sector and was educated at the University of Edinburgh and King s College School of Medicine and Dentistry. Rachel is funded by the BHRC (Leeds).

4 Dr Jayakanth Kankanala JK is working on a number of projects directed towards the design, synthesis and optimisation of small molecules for therapeutic application or their use in the elucidation of biological function. JK joined the group following a PhD in medicinal chemistry (Fishwick, Leeds). JK is funded by the BHRC (Leeds). Dr Emma Prescott Emma is funded on a CRUK Discovery grant held by Andrew McDonald (Leeds) and Richard Foster. She is studying the role of E5 as a potential target for the development of drugs to treat HPV. Dr Katherine Roper Katherine is funded on a Parkinson s UK grant held by Ewan Morrison (Leeds) and Richard Foster. She is investigating the development of a parallelised assay for the identification of inhibitors and activators of parkin to study the role of this protein in the onset of juvenile parkinsonism. PhD students Rachael Tennant Rachael is a 2 nd year PhD candidate researching the development of chemoproteomic approaches to the study of fenretinide action as well as the design of bespoke fenretinide analogues as potential therapeutics to treat Ewing s Sarcoma and related childhood cancers. Rachael s project is managed in collaboration with Sue Burchill (Leeds). Claire Scott Claire is a 1 st year PhD candidate funded by the MRC and jointly supervised by Stephen Griffin (Leeds) and Richard Foster. She is researching the chemistry and biology of p7 ion channel function.

5 Gabriele Stakaityte Gabriele is a 1 st year PhD candidate funded by a BBSRC studentship and jointly supervised by Adrian Whitehouse (Leeds) and Richard Foster. She is studying the biological validation of anti-viral targets for potential therapeutic development. Recruitment We are always interested in recruiting talented new PhD students and postdoctoral associates. Please feel free to contact me for further information on current opportunities. Formal applications for a PhD position may be made through the School of Chemistry's postgraduate admissions office; details of the applications procedure may be found here. Postdoctoral opportunities within the group will be widely advertised. Anyone interested in applying for their own postdoctoral funding please contact me by .