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4 results on '"Woolven, James M."'

1. GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family

Author

Preston, Alex, primary, Atkinson, Stephen J., additional, Bamborough, Paul, additional, Chung, Chun-wa, additional, Gordon, Laurie J., additional, Grandi, Paola, additional, Gray, James R. J., additional, Harrison, Lee A., additional, Lewis, Antonia J., additional, Lugo, David, additional, Messenger, Cassie, additional, Michon, Anne-Marie, additional, Mitchell, Darren J., additional, Prinjha, Rab K., additional, Rioja, Inmaculada, additional, Seal, Jon, additional, Taylor, Simon, additional, Thesmar, Pierre, additional, Wall, Ian D., additional, Watson, Robert J., additional, Woolven, James M., additional, and Demont, Emmanuel H., additional

Published
2020
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2. A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function

Author

Matthews, Laura, Trebble, Peter J., Woolven, James M., Saunders, Ken A., Simpson, Karen D., Farrow, Stuart N., Matthews, Laura C., and Ray, David W.

Subjects
Conformational change, Protein Conformation, Anti-Inflammatory Agents, Pharmacology, Ligands, Dexamethasone, Transactivation, chemistry.chemical_compound, 0302 clinical medicine, Glucocorticoid receptor, Glucocorticoid, Benzoquinones, Molecular Targeted Therapy, 0303 health sciences, Geldanamycin, Ligand (biochemistry), Hsp90, 3. Good health, Cell biology, Protein Transport, GR, Immune System Diseases, Benzamides, medicine.drug, Research Article, Transcriptional Activation, Indazoles, Lactams, Macrocyclic, Biology, Subcellular trafficking, 03 medical and health sciences, Receptors, Glucocorticoid, medicine, Humans, Protein Interaction Domains and Motifs, HSP90 Heat-Shock Proteins, Heat shock protein 90, 030304 developmental biology, Crystal structure, Cell Biology, Androstadienes, Nuclear receptor, chemistry, biology.protein, Fluticasone, 030217 neurology & neurosurgery, HeLa Cells
Abstract

The ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand-binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency, GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, andtranscriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90-binding site. The alteration in the HSP90-binding site was accompanied by resistance to HSP90 antagonism, with persisting transactivation seen after geldanamycin treatment. Taken together, our studies reveal a new mechanism governing GR intracellulartrafficking regulated by ligand binding that relies on a specific surface charge patch within the LBD. This conformational change permits extended GR action, probably because of altered GR-HSP90 interaction. This chemical series may offer anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics. © 2013. Published by The Company of Biologists Ltd.

Published
2013

3. Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

Author

Alder, Catherine M., primary, Ambler, Martin, additional, Campbell, Amanda J., additional, Champigny, Aurelie C., additional, Deakin, Angela M., additional, Harling, John D., additional, Harris, Carol A., additional, Longstaff, Tim, additional, Lynn, Sean, additional, Maxwell, Aoife C., additional, Mooney, Chris J., additional, Scullion, Callum, additional, Singh, Onkar M. P., additional, Smith, Ian E. D., additional, Somers, Donald O., additional, Tame, Christopher J., additional, Wayne, Gareth, additional, Wilson, Caroline, additional, and Woolven, James M., additional

Published
2013
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