Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N‑Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype

• Published in: Journal of medicinal chemistry Vol. 63; no. 17; pp. 9020 - 9044
• Main Authors: Wellaway, Christopher R, Bamborough, Paul, Bernard, Sharon G, Chung, Chun-wa, Craggs, Peter D, Cutler, Leanne, Demont, Emmanuel H, Evans, John P, Gordon, Laurie, Karamshi, Bhumika, Lewis, Antonia J, Lindon, Matthew J, Mitchell, Darren J, Rioja, Inmaculada, Soden, Peter E, Taylor, Simon, Watson, Robert J, Willis, Rob, Woolven, James M, Wyspiańska, Beata S, Kerr, William J, Prinjha, Rab K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.09.2020; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Binding Sites; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - classification; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Cytokines - metabolism; Drug Design; Half-Life; Humans; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Life Sciences & Biomedicine; Male; Mice; Molecular Dynamics Simulation; Pharmacology & Pharmacy; Phylogeny; Protein Domains; Quinolones - chemistry; Quinolones - metabolism; Quinolones - pharmacology; Science & Technology; Transcription Factors - antagonists & inhibitors; Transcription Factors - classification; Transcription Factors - metabolism; POTENT; PROTEIN; CHROMATIN; SMALL-MOLECULE; OPTIMIZATION; IDENTIFICATION; RVX-208; DISCOVERY; FAMILY; BRD4
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00566

The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.