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2 results on '"Daniel Tape"'

1. Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432

Author

Philip G. Humphreys, Niall A. Anderson, Paul Bamborough, Andrew Baxter, Chun-wa Chung, Rosa Cookson, Peter D. Craggs, Toryn Dalton, Julie C. L. Fournier, Laurie J. Gordon, Heather F. Gray, Matthew W. Gray, Richard Gregory, David J. Hirst, Craig Jamieson, Katherine L. Jones, Hripsimee Kessedjian, David Lugo, Grant McGonagle, Vipulkumar K. Patel, Christopher Patten, Darren L. Poole, Rab K. Prinjha, Cesar Ramirez-Molina, Inmaculada Rioja, Gail Seal, Kayleigh A. J. Stafford, Rishi R. Shah, Daniel Tape, Natalie H. Theodoulou, Laura Tomlinson, Sabri Ukuser, Ian D. Wall, Natalie Wellaway, and Gemma White

Subjects
Histones, Protein Domains, Lysine, Drug Discovery, Humans, Molecular Medicine, Ligands, Transcription Factors
Abstract

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

Published
2022
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2. Evidence-based quality indicators for primary healthcare in association with the risk of hospitalisation: a population-based cohort study in Switzerland

Author

Oliver Reich, Thomas Rosemann, Oliver Senn, Eva Blozik, Rahel Meier, Martin Scherer, Carola A Huber, Roland Rapold, Felix Huber, Jan von Overbeck, Felix Schneuwly, and Daniel Tapernoux

Subjects
Medicine
Abstract

Objectives The quality of ambulatory care in Switzerland is widely unknown. Therefore, this study aimed to evaluate the recently proposed quality indicators (QIs) based on a nationwide healthcare claims database and determine their association with the risk of subsequent hospitalisation at patient-level.Design Retrospective cohort study.Setting Inpatient and outpatient claims data of a large health insurance in Switzerland covering all regions and population strata.Participants 520 693 patients continuously insured during 2015 and 2016.Measures A total of 24 QIs were obtained by adapting the existing instruments to the Swiss national context and measuring at patient-level. The association between each QI and hospitalisation in the subsequent year was assessed using multiple logistic regression models.Results The proportion of patients with good adherence to QIs was high for the secondary prevention of diabetes and myocardial infarction (glycatedhaemoglobin (HbA1c) control, 89%; aspirin use, 94%) but relatively low for polypharmacy (53%) or using potentially inappropriate medications (PIMs) in the elderly (PIM, 33%). Diabetes-related indicators such as the HbA1c control were significantly associated with a lower risk of hospitalisation (OR, 0.87; 95% CI, 0.80 to 0.95), whereas the occurrence of polypharmacy and PIM increased the risk of hospitalisation in the following year (OR, 1.57/1.08; 95% CI, 1.51 to 1.64/1.05 to 1.12).Conclusions This is the first study to evaluate the recently presented QIs in Switzerland using nationwide real-life data. Our study suggests that the quality of healthcare, as measured by these QIs, varied. The majority of QIs, in particular QIs reflecting chronic care and medication use, are considered beneficial markers of healthcare quality as they were associated with reduced risk of hospitalisation in the subsequent year. Results from this large practical test on real-life data show the feasibility of these QIs and are beneficial in selecting the appropriate QIs for healthcare implementation in general practice.

Published
2020
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