Steven Charlton

Contact

• workRoom C89c
  Queen's Medical Centre
  Nottingham
  NG7 2UH
  UK
• work0115 8230165
• Steven.Charlton@nottingham.ac.uk

Biography

Prof Charlton joined the University of Nottingham in 2014 where he is Professor of Molecular Pharmacology and Drug Discovery in the School of Life Sciences. Prior to that he spent 16 years in the pharmaceutical industry, both at SmithKline Beecham and Novartis. At Novartis he was Director of Molecular Pharmacology in Respiratory Diseases, leading an assay development and compound profiling team of over 30 scientists providing expert opinion and support for GPCR, ion channel and enzyme projects. He has broad drug discovery experience, ranging from target validation through to leading full lead optimisation programmes to successful clinical proof of concept. He also served on global development teams for several inhaled compounds in Ph2, Ph3 and post-launch, including Onbrez™, Seebri™ and UltiBro™. In 2007 Prof Charlton was awarded Novartis Leading Scientist in recognition of his contribution to the field of quantitative pharmacology and to the Novartis pipeline. Prof Charlton is also Founder and Chief Scientific Officer of Excellerate Biosiences Ltd, a contract research organsiation that provides specialist molecular and cellular pharmacology solutions to the biotech and pharma sector.

Research Summary

Prof Charlton has research interests in two key areas:

Molecular Pharmacology

Prof Charlton is interested in all aspects of the quantitative assessment of ligand-receptor interactions, with particular expertise in the kinetics of ligand binding and signalling. His current research areas include:

1. Developing novel higher throughput methodologies to quantify kinetic rate constants for binding of drugs to proteins. Main focus is GPCRs but also tackling protein-protein interactions and soluble enzymes
2. Investigating biased signaling at GPCRs by investigating spatiotemporal signaling at a single cell and subcellular level using fluorescent and luminescent biosensors
3. Measuring the concentration of drugs at a sub-cellular level to determine the influence of physchem properties and rebinding on observed pharmacology (e.g. kinetics and biased agonism)

Drug Discovery

The main drug discovery focus of the group is the identification of novel therapies to treat remodelling diseases, particularly in the airways (e.g. IPF, PAH, severe asthma and COPD). Prof Charlton's team has expertise in the culture of primary human structural cells from the lung (e.g. lung fibroblasts and smooth muscle cells from both the airway and pulmonary vasculature) and employs both phenotypic and pathway assays in a chemical-biology approach to identify targets capable of preventing or reversing key aspects of tissue remodelling.

Recent Publications

• KOZICZAK-HOLBRO, MAGDALENA, RIGEL, DEAN F., DUMOTIER, BERENGERE, SYKES, DAVID A., TSAO, JEFFREY, NGOC-HONG NGUYEN, BOSCH, JULIAN, JOURDAIN, MARIE, FLOTTE, LUDIVINE, ADACHI, YUICHIRO, KIFFE, MICHAEL, AZRIA, MOISE, FAIRHURST, ROBIN A., CHARLTON, STEVEN J., RICHARDSON, BRIAN P., LACH-TRIFILIEFF, ESTELLE, GLASS, DAVID J., ULLRICH, THOMAS and HATAKEYAMA, SHINJI, 2019. Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived beta(2)-Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 369(2), 188-199
• SYKES, DAVID A., JAIN, PALASH and CHARLTON, STEVEN J., 2019. Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds MOLECULAR PHARMACOLOGY. 96(3), 378-392
• GHERBI, KAROLINA, BRIDDON, STEPHEN J. and CHARLTON, STEVEN J., 2018. Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes SCIENTIFIC REPORTS. 8,
• MICHEL, MARTIN C. and CHARLTON, STEVEN J., 2018. Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path? MOLECULAR PHARMACOLOGY. 93(4), 259-265

• View all publications

• KOZICZAK-HOLBRO, MAGDALENA, RIGEL, DEAN F., DUMOTIER, BERENGERE, SYKES, DAVID A., TSAO, JEFFREY, NGOC-HONG NGUYEN, BOSCH, JULIAN, JOURDAIN, MARIE, FLOTTE, LUDIVINE, ADACHI, YUICHIRO, KIFFE, MICHAEL, AZRIA, MOISE, FAIRHURST, ROBIN A., CHARLTON, STEVEN J., RICHARDSON, BRIAN P., LACH-TRIFILIEFF, ESTELLE, GLASS, DAVID J., ULLRICH, THOMAS and HATAKEYAMA, SHINJI, 2019. Pharmacological Characterization of a Novel 5-Hydroxybenzothiazolone-Derived beta(2)-Adrenoceptor Agonist with Functional Selectivity for Anabolic Effects on Skeletal Muscle Resulting in a Wider Cardiovascular Safety Window in Preclinical Studies JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 369(2), 188-199
• SYKES, DAVID A., JAIN, PALASH and CHARLTON, STEVEN J., 2019. Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds MOLECULAR PHARMACOLOGY. 96(3), 378-392
• MICHEL, MARTIN C. and CHARLTON, STEVEN J., 2018. Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path? MOLECULAR PHARMACOLOGY. 93(4), 259-265
• SYKES, DAVID A, LANE, J ROBERT, SZABO, MONIKA, CAPUANO, BEN, JAVITCH, JONATHAN A and CHARLTON, STEVEN J, 2018. Reply to 'Antipsychotics with similar association kinetics at dopamine D2 receptors differ in extrapyramidal side-effects'.: Nature communications Nature communications. 9(1), 3568
• CIVCIRISTOV S, ELLISDON AM, SUDERMAN R, PON CK, EVANS BA, KLEIFELD O, CHARLTON SJ, HLAVACEK WS, CANALS M and HALLS ML, 2018. Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations. Science signaling. 11(551),
• ROSETHORNE, ELIZABETH M and CHARLTON, STEVEN J, 2018. Airway remodeling disease: primary human structural cells and phenotypic and pathway assays to identify targets with potential to prevent or reverse remodeling. Journal of experimental pharmacology. 10, 75-85
• SYKES, DAVID A. and CHARLTON, STEVEN J., 2018. Single Step Determination of Unlabeled Compound Kinetics Using a Competition Association Binding Method Employing Time-Resolved FRET RATIONAL DRUG DESIGN: METHODS AND PROTOCOLS. 1824, 177-194
• GHERBI, KAROLINA, BRIDDON, STEPHEN J. and CHARLTON, STEVEN J., 2018. Micro-pharmacokinetics: Quantifying local drug concentration at live cell membranes SCIENTIFIC REPORTS. 8,
• SANDHAM DA, BARKER L, BROWN L, BROWN Z, BUDD D, CHARLTON SJ, CHATTERJEE D, COX B, DUBOIS G, DUGGAN N, HALL E, HATTO J, MAAS J, MANINI J, PROFIT R, RIDDY D, RITCHIE C, SOHAL B, SHAW D, STRINGER R, SYKES DA, THOMAS M, TURNER KL, WATSON SJ, WEST R, WILLARD E, WILLIAMS G and WILLIS J, 2017. Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma. ACS medicinal chemistry letters. 8(5), 582-586
• SYKES DA, MOORE H, STOTT L, HOLLIDAY N, JAVITCH JA, LANE JR and CHARLTON SJ, 2017. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nature communications. 8(1), 763
• BERGSDORF, CHRISTIAN, FIEZ-VANDAL, CEDRIC, SYKES, DAVID A., BERNET, PASCAL, AUSSENAC, SONIA, CHARLTON, STEVEN J., SCHOPFER, ULRICH, OTTL, JOHANNES and DUCKELY, MYRIAM, 2016. An Alternative Thiol-Reactive Dye to Analyze Ligand Interactions with the Chemokine Receptor CXCR2 Using a New Thermal Shift Assay Format JOURNAL OF BIOMOLECULAR SCREENING. 21(3), 243-251
• ROSETHORNE EM, BRADLEY ME, GHERBI K, SYKES DA, SATTIKAR A, WRIGHT JD, RENARD E, TRIFILIEFF A, FAIRHURST RA and CHARLTON SJ, 2016. Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β2 Adrenoceptor. Molecular pharmacology. 89(4), 467-75
• KLEIN HERENBRINK C, SYKES DA, DONTHAMSETTI P, CANALS M, COUDRAT T, SHONBERG J, SCAMMELLS PJ, CAPUANO B, SEXTON PM, CHARLTON SJ, JAVITCH JA, CHRISTOPOULOS A and LANE JR, 2016. The role of kinetic context in apparent biased agonism at GPCRs. Nature communications. 7, 10842
• SYKES DA, BRADLEY ME, RIDDY DM, WILLARD E, REILLY J, MIAH A, BAUER C, WATSON SJ, SANDHAM DA, DUBOIS G and CHARLTON SJ, 2016. Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy. Molecular pharmacology. 89(5), 593-605
• DICKSON CJ, HORNAK V, VELEZ-VEGA C, MCKAY DJ, REILLY J, SANDHAM DA, SHAW D, FAIRHURST RA, CHARLTON SJ, SYKES DA, PEARLSTEIN RA and DUCA JS, 2016. Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding. Journal of medicinal chemistry. 59(12), 5780-9
• BRADLEY, M. E., DOMBRECHT, B., MANINI, J., WILLIS, J., VLERICK, D., DE TAEYE, S., VAN DEN HEEDE, K., ROOBROUCK, A., GROT, E., KENT, T. C., LAEREMANS, T., STEFFENSEN, S., VAN HEEKE, G., BROWN, Z., CHARLTON, S. J. and CROMIE, K. D., 2015. Potent and Efficacious Inhibition of CXCR2 Signaling by Biparatopic Nanobodies Combining Two Distinct Modes of Action MOLECULAR PHARMACOLOGY. 87(2), 251-262
• VAUQUELIN, GEORGES, HALL, DAVID and CHARLTON, STEVEN J., 2015. 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models BRITISH JOURNAL OF PHARMACOLOGY. 172(9), 2300-2315
• ROSETHORNE EM, BRADLEY ME, KENT TC and CHARLTON SJ, 2015. Functional desensitization of the β 2 adrenoceptor is not dependent on agonist efficacy. Pharmacology research & perspectives. 3(1), e00101
• TRIFILIEFF A, ETHELL BT, SYKES DA, WATSON KJ, COLLINGWOOD S, CHARLTON SJ and KENT TC, 2015. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model. Toxicology and applied pharmacology. 287(1), 9-16
• BLAKELEY D, SYKES DA, ENSOR P, BERTRAN E, ASTON PJ and CHARLTON SJ, 2015. Simulating the influence of plasma protein on measured receptor affinity in biochemical assays reveals the utility of Schild analysis for estimating compound affinity for plasma proteins. British journal of pharmacology. 172(21), 5037-49
• BERGSDORF C, FIEZ-VANDAL C, SYKES DA, BERNET P, AUSSENAC S, CHARLTON SJ, SCHOPFER U, OTTL J and DUCKELY M, 2015. An Alternative Thiol-Reactive Dye to Analyze Ligand Interactions with the Chemokine Receptor CXCR2 Using a New Thermal Shift Assay Format. Journal of biomolecular screening. 21(3), 243-51
• DALE, PHILIPPA R., CERNECKA, HANA, SCHMIDT, MARTINA, DOWLING, MARK R., CHARLTON, STEVEN J., PIEPER, MICHAEL P. and MICHEL, MARTIN C., 2014. The pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease CURRENT OPINION IN PHARMACOLOGY. 16, 31-42
• MACKENZIE, AMANDA E., CALTABIANO, GIANLUIGI, KENT, TOBY C., JENKINS, LAURA, MCCALLUM, JENNIFER E., HUDSON, BRIAN D., NICKLIN, STUART A., FAWCETT, LINDSAY, MARKWICK, RACHEL, CHARLTON, STEVEN J. and MILLIGAN, GRAEME, 2014. The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35 MOLECULAR PHARMACOLOGY. 85(1), 91-104
• SANDHAM, DAVID A., CHARLTON, STEVEN J., DUBOIS, GERALD, ERPENBECK, VEIT J., SYKES, DAVID and WATSON, SIMON J., 2014. Discovery and characterisation of CRTh2 receptor antagonists suitable for clinical testing in allergic diseases ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY. 248,
• BILL, ANKE, ROSETHORNE, ELIZABETH M., KENT, TOBY C., FAWCETT, LINDSAY, BURCHELL, LYNN, VAN DIEPEN, MICHIEL T., MARELLI, ANTHONY, BATALOV, SERGEY, MIRAGLIA, LOREN, ORTH, ANTHONY P., RENAUD, NICOLE A., CHARLTON, STEVEN J., GOSLING, MARTIN, GAITHER, L. ALEX and GROOT-KORMELINK, PAUL J., 2014. High Throughput Mutagenesis for Identification of Residues Regulating Human Prostacyclin (hIP) Receptor Expression and Function PLOS ONE. 9(6),
• MCKEOWN, STEPHEN C., CHARLTON, STEVEN J., COX, BRIAN, FITCH, HELEN, HOWSON, CHRISTOPHER D., LEBLANC, CATHERINE, MEYER, ARNDT, ROSETHORNE, ELIZABETH M. and STANLEY, EMILY, 2014. Identification of novel IP receptor agonists using historical ligand biased chemical arrays BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. 24(10), 2247-2250
• SYKES, DAVID A., PARRY, CHERYL, REILLY, JOHN, WRIGHT, PENNY, FAIRHURST, ROBIN A. and CHARLTON, STEVEN J., 2014. Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing "Micro-Pharmacokinetic/Pharmacodynamic Relationships" at the beta(2)-Adrenoceptor MOLECULAR PHARMACOLOGY. 85(4), 608-617
• SYKES, DAVID A., RIDDY, DARREN M., STAMP, CRAIG, BRADLEY, MICHELLE E., MCGUINESS, NEIL, SATTIKAR, AFRAH, GUERINI, DANILO, RODRIGUES, INES, GLAENZEL, ALBRECHT, DOWLING, MARK R., MULLERSHAUSEN, FLORIAN and CHARLTON, STEVEN J., 2014. Investigating the molecular mechanisms through which FTY720-P causes persistent S1P(1) receptor internalization BRITISH JOURNAL OF PHARMACOLOGY. 171(21), 4797-4807
• ARNOLD N, BEATTIE D, BRADLEY M, BREARLEY A, BROWN L, CHARLTON SJ, FAIRHURST RA, FARR D, FOZARD J, FULLERTON J, GOSLING M, HATTO J, JANUS D, JONES D, JORDAN L, LEWIS C, MAAS J, MCCARTHY C, MERCER M, OAKMAN H, PRESS N, PROFIT R, SCHUERCH F, SYKES D, TAYLOR RJ, TRIFILIEFF A and TUFFNELL A, 2014. The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist. Bioorganic & medicinal chemistry letters. 24(17), 4341-7
• PORTER DW, BRADLEY M, BROWN Z, CHARLTON SJ, COX B, HUNT P, JANUS D, LEWIS S, OAKLEY P, O'CONNOR D, REILLY J, SMITH N and PRESS NJ, 2014. The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists. Bioorganic & medicinal chemistry letters. 24(15), 3285-90
• ROSETHORNE, ELIZABETH M, KENT, TOBY C, FAWCETT, LINDSAY, VAN DIEPEN, MICHIEL T, MARELLI, ANTHONY, BATALOV, SERGEY, CHARLTON, STEVEN J, GOSLING, MARTIN, GAITHER, L ALEX, RENAUD, NICOLE A, GROOT-KORMELINK, PAUL J, ORTH, ANTHONY P, BURCHELL, LYNN, MIRAGLIA, LOREN and BILL, ANKE, 2014. Colony number and mutation rate obtained by hydroxyl amine mediated mutagenesis. Figshare. 1,
• BRADLEY ME, DOMBRECHT B, MANINI J, WILLIS J, VLERICK D, DE TAEYE S, VAN DEN HEEDE K, ROOBROUCK A, GROT E, KENT TC, LAEREMANS T, STEFFENSEN S, VAN HEEKE G, BROWN Z, CHARLTON SJ and CROMIE KD, 2014. Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action. Molecular pharmacology. 87(2), 251-62
• VAUQUELIN G, HALL D and CHARLTON SJ, 2014. 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models. British journal of pharmacology. 172(9), 2300-15
• NIJMEIJER, S., VISCHER, H. F., SIRCI, F., SCHULTES, S., ENGELHARDT, H., DE GRAAF, C., ROSETHORNE, E. M., CHARLTON, S. J. and LEURS, R., 2013. Detailed analysis of biased histamine H-4 receptor signalling by JNJ 7777120 analogues BRITISH JOURNAL OF PHARMACOLOGY. 170(1), 78-88
• RIAZ, SAJJAD A., CHARLTON, STEVEN J. and TOBIN, ANDREW B., 2013. STUDIES TO VALIDATE A CHEMICAL GENETIC APPROACH TO INVESTIGATE THE M1 MUSCARINIC RECEPTOR JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION. 33(3), 201-201
• MACKENZIE AE, CALTABIANO G, KENT TC, JENKINS L, MCCALLUM JE, HUDSON BD, NICKLIN SA, FAWCETT L, MARKWICK R, CHARLTON SJ and MILLIGAN G, 2013. The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35. Molecular pharmacology. 85(1), 91-104
• RIDDY, D. M., STAMP, C., SYKES, D. A., CHARLTON, S. J. and DOWLING, M. R., 2012. Reassessment of the pharmacology of Sphingosine-1-phosphate S1P3 receptor ligands using the DiscoveRx PathHunter (TM) and Ca2+release functional assays BRITISH JOURNAL OF PHARMACOLOGY. 167(4), 868-880
• NIJMEIJER, SASKIA, VISCHER, HENRY F., ROSETHORNE, ELIZABETH M., CHARLTON, STEVEN J. and LEURS, ROB, 2012. Analysis of Multiple Histamine H-4 Receptor Compound Classes Uncovers G alpha(i) Protein- and beta-Arrestin2-Biased Ligands MOLECULAR PHARMACOLOGY. 82(6), 1174-1182
• FIEZ-VANDAL, CEDRIC, LEDER, LUKAS, FREULER, FELIX, SYKES, DAVID, CHARLTON, STEVEN J., SIEHLER, SANDRA, SCHOPFER, ULRICH and DUCKELY, MYRIAM, 2012. HDL-like discs for assaying membrane proteins in drug discovery BIOPHYSICAL CHEMISTRY. 165, 56-61
• SYKES, DAVID A. and CHARLTON, STEVEN J., 2012. Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting ss(2)-adrenoceptor agonists BRITISH JOURNAL OF PHARMACOLOGY. 165(8), 2672-2683
• NIJMEIJER, S., ROSETHORNE, E. M., VISCHER, H. F., CHARLTON, S. J. and LEURS, R., 2012. LIGAND-DIRECTED H4R SIGNALLING: A STEP FORWARD TO OPTIMIZED H4R DRUGS? INFLAMMATION RESEARCH. 61, S51-S51
• CHARLTON, STEVEN J., 2009. Agonist efficacy and receptor desensitization: from partial truths to a fuller picture BRITISH JOURNAL OF PHARMACOLOGY. 158(1), 165-168