Ann L. Walker, Nicolas Ancellin, Benjamin Beaufils, Marylise Bergeal, Margaret Binnie, Anne Bouillot, David Clapham, Alexis Denis, Carl Haslam, Duncan S. Holmes, Jonathan P. Hutchinson, John Liddle, Andrew McBride, Olivier Mirguet, Christopher G. Mowat, Paul Rowland, Nathalie Tiberghien, Lionel Trottet, Iain Uings, Scott P. Webster, Xiaozhong Zheng, Damian J. Mole,
Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel ...
Tópico(s): Adolescent and Pediatric Healthcare
2017 - American Chemical Society | Journal of Medicinal Chemistry
Olivier Mirguet, Yann Lamotte, Chun‐wa Chung, Paul Bamborough, Delphine Delannée, Anne Bouillot, Françoise Gellibert, Gaël Krysa, Antonia J. Lewis, Jason Witherington, Pascal Huet, Yann Dudit, Lionel Trottet, Edwige Nicodème,
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, ...
Tópico(s): Histone Deacetylase Inhibitors Research
2013 - Wiley | ChemMedChem
John Liddle, Benjamin Beaufils, Margaret Binnie, Anne Bouillot, Alexis Denis, Michael M. Hann, Carl Haslam, Duncan S. Holmes, Jon P. Hutchinson, Michael Kranz, Andrew McBride, Olivier Mirguet, Damian J. Mole, Christopher G. Mowat, Sandeep Pal, Paul Rowland, Lionel Trottet, Iain Uings, Ann L. Walker, Scott P. Webster,
A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo.
Tópico(s): Bipolar Disorder and Treatment
2017 - Elsevier BV | Bioorganic & Medicinal Chemistry Letters
Romain Gosmini, Van Loc Nguyen, Jérôme Toum, Christophe Simon, Jean‐Marie Brusq, Gaël Krysa, Olivier Mirguet, Alizon M. Riou-Eymard, Eric Boursier, Lionel Trottet, Paul Bamborough, Hugh Clark, Chun‐wa Chung, Leanne Cutler, Emmanuel H. Demont, Rejbinder Kaur, Antonia J. Lewis, Mark B. Schilling, Peter E. Soden, S. Taylor, Ann L. Walker, Matthew Walker, Rab K. Prinjha, Edwige Nicodème,
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has ...
Tópico(s): Histone Deacetylase Inhibitors Research
2014 - American Chemical Society | Journal of Medicinal Chemistry
Jonathan T. Seal, Yann Lamotte, Frédéric Donche, Anne Bouillot, Olivier Mirguet, Françoise Gellibert, Edwige Nicodème, Gaël Krysa, Jorge Kirilovsky, Sören Beinke, Scott McCleary, Inma Rioja, Paul Bamborough, Chun‐wa Chung, Laurie Gordon, Toni Lewis, Ann L. Walker, Leanne Cutler, David Lugo, David M. Wilson, Jason Witherington, Kevin Lee, Rab K. Prinjha,
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.
Tópico(s): RNA Interference and Gene Delivery
2012 - Elsevier BV | Bioorganic & Medicinal Chemistry Letters
Damian J. Mole, Scott P. Webster, Iain Uings, Xiaozhong Zheng, Margaret Binnie, Kris Wilson, Jonathan P. Hutchinson, Olivier Mirguet, Ann L. Walker, Benjamin Beaufils, Nicolas Ancellin, Lionel Trottet, Véronique Bénéton, Christopher G. Mowat, Martin Wilkinson, Paul Rowland, Carl Haslam, Andrew McBride, Natalie Homer, James Baily, Matthew G.F. Sharp, O. James Garden, Jeremy Hughes, Sarah Howie, Duncan S. Holmes, John Liddle, John P. Iredale,
Blocking the enzyme KMO with a small molecule reduces the levels of toxic tryptophan metabolites and reduces multiple extrapancreatic organ failure in a rat model of acute pancreatitis. Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive ...
Tópico(s): Stress Responses and Cortisol
2016 - Nature Portfolio | Nature Medicine
Chun‐wa Chung, Hervé Coste, Julia H. White, Olivier Mirguet, Jonathan I. Wilde, Romain Gosmini, Chris J. Delves, Sylvie M. Magny, Robert L. Woodward, Stephen Hughes, Eric Boursier, Helen R. Flynn, Anne Bouillot, Paul Bamborough, Jean‐Marie Brusq, Françoise Gellibert, Emma J. Jones, Alizon M. Riou, Paul Homes, Sandrine Martin, Iain Uings, Jérôme Toum, Catherine A. Clément, Anne-Bénédicte Boullay, Rachel L. Grimley, Florence Blandel, Rab K. Prinjha, Kevin Lee, Jorge Kirilovsky, Edwige Nicodème,
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization ...
Tópico(s): Ubiquitin and proteasome pathways
2011 - American Chemical Society | Journal of Medicinal Chemistry
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2019 - Cambridge University Press | Annales Histoire Sciences Sociales
Céline Legros, Paul Ratcliffe, Vanessa Porkolab, Michèle Modugno, Olivier Mirguet,
... step of drug discovery. Citation Format: Celine Legros, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, Olivier Mirguet. First reported PIM kinase degraders: Design, profiling & optimization [ ...
Tópico(s): Peptidase Inhibition and Analysis
2024 - American Association for Cancer Research | Cancer Research
Olivier Mirguet, Romain Gosmini, Jérôme Toum, Catherine A. Clément, Mélanie Barnathan, Jean‐Marie Brusq, J.E. Mordaunt, Richard M. Grimes, Miriam C. Crowe, Olivier Pineau, Myriam Ajakane, Alain Daugan, Philip D. Jeffrey, Leanne Cutler, Andrea Haynes, Nicholas Smithers, Chun‐wa Chung, Paul Bamborough, Iain Uings, Antonia J. Lewis, Jason Witherington, Nigel J. Parr, Rab K. Prinjha, Edwige Nicodème,
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear ...
Tópico(s): Multiple Myeloma Research and Treatments
2013 - American Chemical Society | Journal of Medicinal Chemistry
J. Galland, H. De Boysson, Ariane Normand, Lina Mroueh, V. Hess, C. Rode, Paul Maurice Conway, Jean-Paul Bled, A. Mirguet, L. Donier, Elisa Van der Elst, E. Le Peillet Feuilet, L. Etienne,
Les maladies rares ont un impact médical, social et économique significatif en Europe. En France, elles représentent un enjeu majeur de santé publique car les 7000 maladies rares identifiées à ce jour atteignent plus de 3 millions de personnes soit 4,5 % de la population générale. Ces affections sont souvent chroniques et les patients atteints sont confrontés à de nombreux obstacles à commencer par une importante errance diagnostique. En moyenne, une maladie rare est diagnostiquée après une errance ...
Tópico(s): Public Health and Social Inequalities
2024 - Elsevier BV | La Revue de Médecine Interne
Anne Mirguet, Florence A. Aeschlimann, I. Lemelle, R. Jaussaud, Paul Decker, T. Moulinet, S. Mohamed, Pierre Quartier, Michaël Hofer, Olivia Boyer, Alexandre Bélot, Aurélie Hummel, N. Costedoat‐Chalumeau, Brigitte Bader‐Meunier,
Data on the long-term outcome of patients with childhood-onset Systemic Lupus Erythematosus (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity. We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, ...
Tópico(s): Atherosclerosis and Cardiovascular Diseases
2024 - Oxford University Press | Lara D. Veeken