Led by Prof Keith Channon, will incorporate the best of our hypothesis driven, disease mechanism research where efforts are specifically targeted to discovery of tractable targets and medicinal chemistry approaches (existing partnerships with Chemistry and the Target Discovery Institute and new links with the Structural Genomics Consortium and the Interdisciplinary Science building).
The vision for the Oxford BHF CRE’s Target Discovery Theme is the development of novel therapeutics for cardiovascular medicine,
We will use our expertise, capabilities and resources to (a) discover and validate novel targets and small molecule probes in human biological systems; (b) identify existing clinical molecules for repurposing, and generate new clinical molecules and biologics, and, (c) undertake early phase proof-of concept clinical studies with a focus on biological and imaging-derived mechanistic endpoints in highly characterised and stratified patient groups, to enable statistically powerful efficacy testing.
The Oxford BHF CRE’s Target Discovery Theme will establish a capability ‘pipeline’ of target discovery, drug development and early phase clinical trials that will enable both discovery and development of new molecules, and exploratory development of existing molecules towards clinical application in areas such as:
Epigenetic modifiers have been identified as powerful therapeutic targets in cancer, neuroscience and immunology, but remain relatively unexplored in cardiometabolic disease. Epigenetic modification is a critical factor in programming gene expression and cellular differentiation that underlies cardiometabolic disease susceptibility at the cellular, tissue and patient-specific levels.
G Protein Coupled Receptor (GPCR) signalling incorporates many druggable targets. However, many ‘orphan’ GPCRs mediate new signalling paradigms, e.g. free fatty acids and other small ligands related to cardiometabolic disease and ‘immunometabolism’. Identifying new GPCR targets, and understanding new aspects of GPCR biology, will open up new approaches to therapeutic intervention.
Biologics and Peptido-mimetic Drugs will provide new tool compounds and potential therapeutics target protein-protein interactions including in-house peptide synthesis, isothermal titration calorimetry and biolayer interferometry for protein-protein interactions. A pipeline to identify novel biologicals (‘Bug-to-Drug’) uses bioinformatics, high-throughput ‘Golden Gate’ cloning, and yeast surface display technology to create libraries for rapid screening.
Metabolism, Inflammation and Redox Signalling provide fertile opportunities for testing repurposed drugs for rapid clinical benefit, because many existing drugs have potential efficacy that has not realised optimal clinical benefit due to lack of appropriate targeting to disease mechanism and/or clinical indication. Integrated approaches to mechanistic staging in individual patients will include transcriptomics/epigenomics and state of the art imaging, integrated over time.
Experimental Medicine and POC Clinical Trials will enable early testing of clinical effectiveness, achieving biological and statistical power through patient selection/stratification and through mechanistic endpoints with advanced phenotyping tools in highly-characterised patient cohorts. Internationally-leading cardiovascular imaging include cardiac CT, cardiac MR, spectroscopy and hyperpolarised isotope imaging.