Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins

• Published in: Journal of medicinal chemistry 2020-09, Vol.63 (17), p.9070-9092
• Main Authors: Preston, Alex, Atkinson, Stephen, Bamborough, Paul, Chung, Chun-wa, Craggs, Peter D, Gordon, Laurie, Grandi, Paola, Gray, James R. J, Jones, Emma J, Lindon, Matthew, Michon, Anne-Marie, Mitchell, Darren J, Prinjha, Rab K, Rianjongdee, Francesco, Rioja, Inmaculada, Seal, Jonathan, Taylor, Simon, Wall, Ian, Watson, Robert J, Woolven, James, Demont, Emmanuel H
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - metabolism; Animals; Benzene Derivatives - chemistry; Binding Sites; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Crystallography, X-Ray; Drug Design; Humans; Microsomes, Liver - metabolism; Molecular Dynamics Simulation; Protein Domains; Quantum Theory; Rats; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00605

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.