The LIMM Chemical Biology programme was established in the Section of Experimental Therapeutics in November 2006. The objectives of this programme are several fold, ranging from target identification, to target validation and to small molecule drug development.
We aim to develop methods for validation of potential drug targets in human diseases, in particular cancer, using in vivo models recapitulating primary events in disease aetiology; to develop lead reagents for determining sites on target molecules appropriate for small molecule drug interaction; to assess options for targeting protein-protein interactions inside cells; and to develop small molecule drug-like compounds for therapeutics leads (our future lead optimization strategy is through establishment of spin-out companies or out-licensing). We work with macromolecular drugs (macrodrugs) such as small antibody fragments (single variable region domains) designed to bind target antigens inside cells and peptide aptamers with optimized peptide display scaffolds, combining crystal and NMR structural data with biological assays. We use high throughput in silico small molecule library screening to develop lead small molecule compounds that mimic macrodrug-antigen binding sites. In addition, we develop and use in vitro and cell-based assays for small molecule library high throughput screening.
From November 2009, the Leeds Institute of Molecular Medicine will be a Member of the UK Drug Discovery Consortium (UKDDC) allowing us to access UKDDC information on compound library construction, target selection and hit to candidate processes as well as accessing small molecule libraries where appropriate. This will be invaluable for the Institute’s aim to develop new drugs against human diseases by providing a forum for LIMM Chemical Biology programme scientists to interact with other UK scientists involved in drug development programmes. More information will be available shortly when our password protected area of the UKDDC has been established.
The main therapeutic targets of interest are proteins which are altered or aberrantly expressed in cancer. In particular, we work on chromosomal translocation products (such as fusion proteins), proteins abnormally expressed in the pre-invasive stages of cancer (in conjunction with the YCR Centre for Pre-Cancer Genomics) and transcription or signaling proteins that function through protein-protein interactions. We work in collaboration with colleagues in the University of Leeds School of Chemistry (Professors Johnson & Grigg and Dr Fishwick) and the Astbury Structural Biology Centre (Professor Steve Homans and Simon Phillips).