Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening
| Autor: | Patricia F Medeiros, Mythily Vimal, Vipulkumar Kantibhai Patel, John Evans, Neil R Carlson, Antonia J. Lewis, Paul Bamborough, Katherine L Jones, Jane E Smith, Michael O'Sullivan, Scott McCleary, Darren J. Mitchell, Heather Barnett, Chun-wa Chung, Gang Yao, Anthony W. J. Cooper, Rab K. Prinjha, Laurie Gordon, Mahnoor Mahmood, Peter D. Craggs, Isobel L Harada, Rino A Bit, Natalie Wellaway, Armelle Le Gall, Robert J. Watson, Tony W Dean, Dominique Amans, Ian D. Wall, Kayleigh A J Stafford, Dave Lugo, Matthew J Lindon, Rishi R Shah, David Jonathan Hirst, Chris Patten, Darren L Poole, Jack A Brown, Philip G Humphreys, Robert P Davis, Christopher Roland Wellaway, Pamela J Thomas |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Models Molecular Benzimidazole Lysine Drug Evaluation Preclinical Computational biology Crystallography X-Ray Small Molecule Libraries Mice chemistry.chemical_compound In vivo Histone tails Drug Discovery Leukocytes Animals Humans Chemokine CCL2 Therapeutic strategy Interleukin-6 Chemistry Anti-Inflammatory Agents Non-Steroidal Proteins Drug Synergism Epigenome Small molecule High-Throughput Screening Assays Bromodomain Molecular Medicine Benzimidazoles Protein Processing Post-Translational |
| Zdroj: | Journal of Medicinal Chemistry. 63:714-746 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01670 |
| Popis: | The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose. |
| Databáze: | OpenAIRE |
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