Professor Barry Potter, Dr Andrew Riley
(Pharmacology Department; Medicinal Chemistry & Drug Discovery Group)
Cell Signalling, Drug Discovery & Medicinal Chemistry: Work concerns the design, synthesis and biological evaluation of active organic molecules at the interfaces of Chemistry & Biology, ultimately aimed at the dissection of biological mechanisms through chemical biological intervention or, at the interface of Chemistry & Medicine, through intelligent drug design & discovery with the aim of moving translationally from 'concept to clinic'. A unifying general theme is centered around cellular signalling processes and concerns both entities involved in the chemistry of signal transduction processes, particularly those involving cyclitol and nucleotide-based second messengers signalling through the elevation of intracellular Ca 2+, and endocrine signalling and its modulation in oncology and endocrinology. Synthetic cyclitol, carbohydrate, nucleotide and medicinal chemistry is underpinned by biochemical assays, protein crystallography and by in silico methods for structure-based design. The two main themes are:
The Chemistry of Signal Transduction:
Inositol phosphate-mediated cellular signalling and the roles of the higher inositol polyphosphates; Cyclic ADP-ribose - a nucleotide second messenger; ADP-ribose, a nucleotide second messenger & TRPM2; NAADP - a nucleotide second messenger.
Anticancer Drug Design, Discovery & Translational Medicine.
Drug design for hormone-dependent and independent diseases; inhibitor design for sulfatases; design of multi-targeting drug candidates for oncology.
2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist. R Fliegert, A Bauche, A-M Wolf Pérez, J M Watt, M D Rozewitz, R Winzer, M Janus, F Gu, A Rosche, A Harneit, M Flato, C Moreau, T Kirchberger, V Wolters, B V L Potter and Andreas H Guse. Nature Chem Biol (2017) 13, 1036-1044.
Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. P J Watson, C J Millard, A M Riley, N S Robertson, L C Wright, H Y Godage, S M Cowley, A G Jamieson, B V L Potter and J W R Schwabe Nature Communications (2016) 7, 11262.
The “Other” Inositols and Their Phosphates: Synthesis, Biology & Medicine (with Recent Advances in myo-Inositol Chemistry). M P Thomas, S J Mills & B V L Potter Angewandte Chemie Int Edn Eng (2016) 55, 1614-1650.
Crystal Structures of Type-II Inositol Polyphosphate 5-Phosphatase INPP5B with synthetic inositol polyphosphate surrogates reveal new mechanistic insights for the inositol 5-phosphatase family. S J Mills, C Silvander, G Cozier, L Trésaugues, P Nordlund, and B V L Potter Biochemistry (2016) 55, 1384-1397.
Synthetic tools for studying the chemical biology of InsP8. A M Riley, H Wang, S B Shears and B V L Potter Chem Comm (2015) 51, 12605-12608.
Discovery and Development of the Aryl O-Sulfamate Moiety for Oncology and Women’s Health. M P Thomas & B V L Potter J Med Chem (2015) 58, 7634-7658.