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BiosketchProfessor Potter studied chemistry as an Open Exhibitioner at Oxford University, graduating with first class honours and winning the Part II Thesis prize in Organic Chemistry. He completed his DPhil at Oxford in Bioorganic/Biological Chemistry as a Graduate Scholar and later Junior Research Fellow, working on the stereochemistry of enzyme-catalysed phosphoryl transfer reactions, developing the now textbook [16O,17O,18O] oxygen chiral phosphate ester approach that he applied to kinase, phosphatase and mutase enzyme mechanisms. After postdocs at Oxford and at the Max-Planck-Institute for Experimentelle Medizin in Goettingen, Germany, as Royal Society European Exchange Fellow and later Wissenschaftlicher Mitarbeiter der Max-Planck Gesellschaft, he became Lecturer in Biological Chemistry at Leicester University and won a Lister Institute of Preventive Medicine Fellowship. In 1990 he moved to the chair of Medicinal Chemistry at the University of Bath, as Lister Institute Research Professor where he holds the Established Chair in the Department of Pharmacy & Pharmacology, as Head of the Medicinal Chemistry Section. His fields of research activity are at the interface between Chemistry & Biology and Chemistry & Medicine ie Medicinal & Biological Chemistry, Chemical Biology, Mechanistic Enzymology, Signal Transduction Chemistry, Anticancer Drug Design & Discovery and Translational & Molecular Medicine. Particular interests are in the chemistry of cellular signalling, using carbohydrate, nucleotide and cyclitol chemistry to explore the pharmacology of second messengers that mobilise intracellular calcium, such as inositol 1,4,5-trisphosphate (IP3), cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). His research group has developed numerous structurally-modified ligands in all classes that have found widespread uses as pharmacological and chemical biological tools, some with proven activity in disease models. In Medicinal Chemistry, inter alia, he has pioneered a novel pharmacophore in drug design and, unusually within an academic setting, has brought several compounds from novel therapeutic concept to multiple Phase I and II human clinical trials (15 to date) with evidence of efficacy, most notably in the cancer field directed against steroid sulfatase and in women’s health. He co-founded the university spin out company Sterix Ltd that was acquired by major pharma; he is a Fellow of the Royal Society of Chemistry, the Society of Biology, the Institute of Directors and the Royal Society of Arts and has published over 450 research articles with ca 200 granted patents from many diverse families. He was elected to Membership of the Lister Institute of Preventive Medicine in 1995. He served on the BBSRC Intracellular Signalling Programme Committee (1992–1996) and the EPSRC Synthetic and Biological Chemistry College (1995–1997). He is a member of the Biochemical Society, the American Association for Cancer Research and the American Chemical Society and was a committee member of the Society for Medicines Research (2002-2006). He was a member of the HEFCE Pharmacy/Pharmacology Panel for the RAE2001 and RAE2008 exercises and the Research Excellence Framework (REF) Expert Group Panel 2009 and is a current member of the Molecules, Genes & Cells Funding Panel of the Wellcome Trust. He is on the editorial boards of the Journal of Medicinal Chemistry, Molecular Cancer Therapeutics, Perspectives in Medicinal Chemistry and Future Medicinal Chemistry, has served on the boards of Carbohydrate Research, Biochemical Journal, Current Organic Synthesis and Drug Design & Discovery, and is currently Associate Editor of the Journal of Steroid Biochemistry & Molecular Biology and Editor of Biochemical Journal's BJChemBio. He received a DSc from Oxford in 1993 and is Visiting Professor of Medicinal Chemistry at Oxford University and Associate Member, Department of Pharmacology, Oxford. He is named in the “H-index ranking of living chemists” listing. Professor Potter was the recipient of the Royal Society of Chemistry UCB-Celltech Industrially Sponsored Award and Medal for Chemical Biology for 2007, the Royal Society of Chemistry George and Christine Sosnovsky Award & Medal for cancer medicinal chemistry for 2007/8 with an RSC Endowed Lectureship, the Royal Society of Chemistry Biological & Medicinal Chemistry Sector’s Malcolm Campbell Memorial Prize & Medal for 2009 and the GlaxoSmithKline International Achievement Award for 2009. He was elected to Fellowship of the Academy of Medical Sciences in 2008 and in 2009 to Membership of the Academia Europaea.
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Research Interests
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Research Interests: Biological and Medicinal Chemistry of Signalling Molecules Research is centred around four main areas of synthetic Medicinal and Biological Chemistry and Chemical Biology. All projects concern the design, synthesis and biological evaluation of active organic molecules at the interface of Chemistry and Biology, ultimately aimed at the dissection of biological mechanisms through chemical biological intervention, or at the interface of Chemistry and Medicine through intelligent drug design & discovery with the aim of moving translationally from 'concept to clinic'. A unifying general biological theme concerns both the entities involved in endocrine signalling and their modulation in oncology, as well as intracellular signal transduction processes in particular. Where possible, synthesized ligands are co-crystallised with relevant binding proteins for structure-based design. Examples of solved X-ray structures from the group are shown. The four main themes are: Inositol phosphate mediated cellular signalling Cyclic ADP-ribose - a new second messenger NAADP - a new second messenger Steroid-based enzyme inhibitors as novel therapeutic agents Dehydrogenase Inhibition: 17β-Hydroxysteroid dehydrogenase is a novel target for anticancer drug design of hormone dependent tumours and for endometriosis. Potent and selective low nanomolar inhibitory druglike candidates have been designed and are under evaluation. Efforts directed at novel approaches to diabetes and metabolic syndrome are being pursued by inhibition of the enzyme target 11β-hydroxysteroid dehydrogenase. Nanomolar inhibitors active on the whole cell are being designed, synthesized and evaluated. Biological evaluation is carried out in collaboration with Imperial College London and Ipsen Novel antagonists at the nicotinic acetylcholine receptor (with Dr I S Blagbrough) Research is centred around the exploitation of a very potent natural product alkaloid lead compound, methyllycaconitine, whose value was apparent in Roman times, for the design and synthesis of novel small molecule antagonists at the nicotinic acetylcholine receptor. The project employs a range of synthetic techniques to prepare novel polycycles, which are evaluated for nicotinic antagonist potency in the Department of Biology and Biochemistry (with Professor S J Wonnacott). Potent small molecule mimics have now been designed that have potential for use in neurodegenerative diseases and as safer insecticides.
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Selected Recent Publications:
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2010Highly Potent First Dual Aromatase-Steroid Sulfatase Inhibitors based on a Biphenyl Template. Class III β-tubulin, expression and in vitro resistance to microtubule targeting agents. A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6 pentakisphosphate. 2009Structural Basis for Enzymatic Evolution from a Dedicated ADP-ribosyl cyclase to a Multiple Functional NAD Hydrolase. The behaviour of inositol 1,3,4,5,6-pentakisphosphate in the presence of the major biological metal cations. Determination of the absolute configuration of aromatase and dual aromatase-sulfatase inhibitors by vibrational and electronic circular dichroism spectral analysis. Synthetic partial agonists reveal key steps in IP3 receptor activation. 8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist. NAADP mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist. The development of steroid sulfatase inhibitors for hormone-dependent cancer therapy. Discovery of Adamantyl Amides as Novel Selective Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1. The Design of Novel 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibitors. Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3. BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure. 20082-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer. S L C Tagg, P A Foster, M P Leese, B V L Potter, M J Reed, A Purohit and S P Newman, Brit J Cancer (2008) 99, 1842-1848. Effects of C-17 Heterocyclic substituents on the anticancer activity of 2-ethylestra 1,3,5(10)-triene-3-O-sulfamates: Synthesis, in vitro evaluation and computational modelling. Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities. The in vivo properties of STX243: a potent angiogenesis inhibitor. A new therapeutic strategy against hormone-dependent breast cancer: The preclinical development of a dual aromatase and sulfatase inhibitor. The use of steroid sulfatase inhibitors as a novel therapeutic strategy against hormone dependent endometrial cancer. Steroid sulfatase inhibitors and endometrial cancer. Efficacy of three potent steroid sulfatase inhibitors: Pre-clinical investigations for their use in the treatment of hormone-dependent breast cancer. 2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. Design and synthesis of 4”,6”-unsaturated cyclic ADP-carbocyclic ribose, a Ca2+-mobilizing agent selectively active in T cells. Steroid sulphatase inhibitors as a target for the topical treatment of skin disorders. Benzene Polyphosphates as tools for cell signaling: interaction with the PH domain of protein kinase Ba and inhibition of inositol 1,4,5-trisphosphate 5-phosphatase. Chiral Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole Template: Synthesis, Absolute Configuration and In Vitro Activity. Anti-cancer steroid sulfatase inhibitors: synthesis, in vitro and in vivo activities, molecular modelling and protein crystallography of a potent fluorinated second-generation agent. Inhibition of steroid sulphatase activity in endometriotic implants by 667COUMATE: a potential new therapy. STX140 is efficacious in vitro and in vivo in taxane resistant breast carcinoma cells. Direct Evidence for ArO-S Bond Cleavage upon Inactivation of Pseudomonas aeruginosa Arylsulfatase by Aryl Sulfamates. 2-Position Base-Modified Analogs of Adenophostin A as High-Affinity Agonists of the D-myo-Inositol Trisphosphate Receptor: In Vitro Evaluation and Molecular Modeling. Chemoenzymatic synthesis of 7-deaza cyclic adenosine 5'-diphosphate ribose analogues, membrane permeant modulators of intracellular calcium release. 17ß-Hydroxysteroid dehydrogenase type 1 and not type 12 is a target for endocrine therapy of hormone-dependent breast cancer. 2'-Deoxy Cyclic Adenosine 5'-Diphosphate Ribose Derivatives: Importance of a 2' Hydroxyl Motif for the Antagonistic Activity of 8-Substituted cADPR Derivatives. Structure-Activity Relationships of C-17 Cyanated Estratrienes as Anti-cancer agents. Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1. Novel Non-steroidal Aromatase Inhibitors Based On a Biphenyl Scaffold: synthesis, in vitro SAR and molecular modelling. Novel Inhibitors of 17ß Hydroxysteroid Dehydrogenase Type 1: Templates for Design. 2007The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers. Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog. 3,17-Disubstituted 2-alkyestra-1,3,5(10)-trien-3-ol derivatives: synthesis, in vitro and in vivo anti-cancer activity. Dual aromatase-steroid sulfatase inhibitors. Novel inositol phospholipid headgroup surrogate crystallised in the PH domain of protein kinase Ba. Nicotinamide 2-fluoroadenine dinucleotide unmasks the NAD+ glycohydrolase activity of Aplysia Californica adenosine 5'-diphosphate-ribosyl cyclase. Biphenyl-2,3’4,5’,6-pentakisphosphate, a novel inositol polyphosphate surrogate, inhibits the activity of two inositide 5-phosphatases and modulates Ca2+ responses in rat hepatocytes. Rapid and efficient routes to phosphatidylinositol 3,4,5-trisphosphates via myo-inositol orthobenzoate. 20062-Substituted estradiol bis-sulfamates, multi-targeted anti-tumor agents: Synthesis, in vitro SAR, protein crystallography and in vivo activity. 3-Hydroxybenzene 1,2,4-trisphosphate, a novel second messenger mimic and unusual substrate for type-I myo-inositol 1,4,5-trisphosphate 5-phosphatase: Synthesis and physicochemistry. Cellular effects and metabolic stability of N1-cyclic inosine diphosphoribose and its derivatives. A Systematic study of C-glucoside trisphosphates as myo-inositol trisphosphate receptor ligands. Synthesis of -C-glucoside trisphosphates based on the conformational restriction strategy. Design and synthesis of 5'-deoxy-5'-phenyladenophostin A, a highly potent IP3 receptor ligand. Focused libraries of 16 substituted estrone derivatives and modified E-ring steroids: Inhibitors of 17 -hydroxysteroid dehydrogenase type 1. Guanophostin A: Synthesis and evaluation of a high affinity agonist of the D-myo-inositol 1,4,5 trisphosphate receptor. Regioselective hydrolysis of myo-inositol 1,3,5-orthobenzoate via a 1,2-Bridged 2-phenyl-1',3'-dioxolan-2'-ylium ion provides a rapid route to the anticancer agent Ins(1,3,4,5,6)P5. Structural determinants for N1/N7 cyclization of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) derivatives by ADP-ribosyl cyclase from Aplysia Californica: Ca2+-mobilizing activity of 8-substituted cyclic inosine 5'-diphosphoribose analogues in T-lymphocytes. Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release. Rapid microwave-assisted reductive amination of ketones with anilines. scyllo-Inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: chemical synthesis, physicochemistry and biological applications. In vivo efficacy of STX213, a second generation steroid sulfatase inhibitor for hormone-dependent breast cancer therapy. Phase I study of STX64 (667 Coumate) in breast cancer patients: the first study of a steroid sulphatase inhibitor. On the contribution of stereochemistry to ITPK1 specificity: Ins(1,4,5,6)P4 is not a physiologic substrate. Chiral desymmetrisation of myo-inositol 1,3,5-orthobenzoate gives rapid access to precursors for second messenger analogues. Modification of estrone at the 6, 16, 17 positions: Novel potent inhibitors of 17 -hydroxysteroid dehydrogenase type 1. Unusual entry to the novel 8-halo-N1-ribosyl hypoxanthine system by degradation of a cyclic adenosine-5'-diphosphate ribose analogue. 2005Steroid sulfatase: Molecular biology, regulation and inhibition Crystal structure of human carbonic anhydrase II at 1.95 Å resolution in complex with 667-coumate, a novel anti-cancer agent. Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity. First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors. Novel and potent 17 -hydroxysteroid dehydrogenase type 1 inhibitors. Rapid synthetic route towards structurally modified derivatives of cyclic adenosine 5'-diphosphate ribose. Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca2+-mobilizing second messenger. Structure-activity relationship of the N1-ribose moiety. Interaction of the catalytic domain of Inositol 1,4,5-trisphosphate 3-kinase A with inositol phosphate analogues. A-ring substituted estrogen-3-O-sulfamates: Potent multi-targeted anti-cancer agents. E-Ring modified steroids as novel potent inhibitors of 17 -hydroxysteroid dehydrogenase type 1. Inhibition of the Phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumour effects.
2004Inhibition of in vitro angiogenesis by 2-methoxy- and 2-ethyl-estrogen sulfamates. Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor or carbonic anhydrases and steroid sulfatase. Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Dimers of D-myo-inositol 1,4,5-trisphosphate: Design, synthesis and interaction with Ins(1,4,5)P3 receptors. 2-O-(2-Aminoethyl)-myo-inositol 1,4,5-trisphosphate as a novel ligand for conjugation: physicochemical properties and synthesis of a new Ins(1,4,5)P3 affinity matrix. 2-Alkylsulfanyl estrogen derivatives: synthesis of a novel class of multi-targeted anti-tumour agents. 2-MeOE2bisMATE induces caspase-dependent apoptosis in CAL51 breast cancer cells and overcomes resistance to TRAIL via cooperative activation of caspases. Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells. Inositol trisphosphate analogues selective for types I and II inositol trisphosphate receptors exert differential effects on vasopressin-stimulated Ca2+ inflow and Ca2+ release from intracellular stores in rat hepatocytes. Novel 18 -Glycyrrhetinic acid analogues as potent and selective inhibitors of 11 -hydroxysteroid dehydrogenases. Chemical synthesis of the second messenger nicotinic acid adenine dinucleotide phosphate by total synthesis of nicotinamide adenine dinucleotide phoshate. Regulation of casein kinase-2 (CK2) activity by inositol phosphates. D-6-Deoxy myo-inositol 1,3,4,5-tetrakisphosphate, a mimic of D-myo-inositol 1,3,4,5-tetrakisphosphate: biological activity and pH-dependent conformational properties. Aplysia californica mediated cyclisation of novel 3'-modified NAD analogues: A role for hydrogen bonding in the recognition of cyclic adenosine 5'-diphosphate ribose. 2003Synthesis and Ca2+ mobilising activity of purine-modified mimics of adenophostin A: A model for the adenophostin-Ins(1,4,5)P3 receptor interaction. Identification of mammalian Vps24p as an effector of phosphatidylinositol 3,5 bisphosphate-dependent endosome compartmentalization. Convergent synthesis and unexpected Ca2+-mobilizing activity of the 8-substituted analogues of cyclic ADP-carbocyclic ribose, a stable mimic of Ca2+-mobilizing second messenger cyclic ADP-ribose. First enzymatic synthesis of an N1-cyclised cADPR (cyclic-ADP ribose) analogue with an hypoxanthine partial structure: discovery of a membrane permeant cADPR agonist. First dual aromatase-steroid sulfatase inhibitor. D-ring modified estrone derivatives as novel potent inhibitors of steroid sulfatase. 2002Estrone 3-sulfate mimics, inhibitors of estrone sulfatase activity: Homology model construction and docking studies Interactions of inositol 1,4,5-trisphosphate receptors with synthetic poly(ethylene glycol)-linked dimmers of IP3 suggest close spacing of the IP3-binding sites. Novel hydrolysis-resistant analogues of cyclic ADP-ribose: Modification of the "northern" ribose and calcium release activity. Regulation of Ins(3,4,5,6)P4 signaling by a reversible kinase/phosphatase. 2001Total synthesis of nucleobase-modified adenophostin A mimics. Bicyclic analogs of D-myo-inositol 1,4,5-trisphosphate related to adenophostin A: Synthesis and biological activity. Structural determinants of adenophostin A activity at inositol trisphosphate receptors. 2000Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an essential regulator of T-lymphocyte Ca2+-signaling. Synthesis of potent agonists of the D-myo-inositol 1,4,5-trisphosphate receptor based on clustered disaccharide polyphosphate analogues of adenophostin A. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. 1999Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus. 1998Steroidal and non-steroidal sulfamates as potent inhibitors of steroid sulfatase. A conformationally restricted cyclic phosphate analogue of inositol trisphosphate: synthesis and physicochemical properties Total synthesis from D-xylose of chiral, ring-contracted 1D-myo-inositol 1,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate analogues with C-2 excised. 1997Disaccharide polyphosphates based upon adenophostin A activate hepatic d-myo-inositol 1,4,5-trisphosphate receptors. Structural analogues of D-myo- inositol 1,4,5-trisphosphate and adenophostin A: Recognition by cerebellar and platelet inositol 1,4,5-trisphosphate receptors. Rapid synthesis of the enantiomers of myo-inositol 1,3,4,5-tetrakisphosphate by direct chiral desymmetrization of myo-inositol orthoformate. 1996Isotopic enrichment by asymmetric deuteriation. An investigation of the synthesis of deuteriated (S)-(-)-methylsuccinic acids from itaconic acid.
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