Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins

• Published in: Journal of medicinal chemistry Vol. 59; no. 4; pp. 1634 - 1641
• Main Authors: Raux, Brigitt, Voitovich, Yuliia, Derviaux, Carine, Lugari, Adrien, Rebuffet, Etienne, Milhas, Sabine, Priet, Stéphane, Roux, Thomas, Trinquet, Eric, Guillemot, Jean-Claude, Knapp, Stefan, Brunel, Jean-Michel, Fedorov, Alexey Yu, Collette, Yves, Roche, Philippe, Betzi, Stéphane, Combes, Sébastien, Morelli, Xavier
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.02.2016; Amer Chemical Soc
• Subjects: Acetylation; Biochemistry, Molecular Biology; Chemistry, Medicinal; Drug Discovery; Humans; Life Sciences; Life Sciences & Biomedicine; Models, Molecular; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Pharmacology & Pharmacy; Protein Structure, Tertiary - drug effects; Quantitative Methods; Science & Technology; Structural Biology; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - metabolism; Xanthines - chemistry; Xanthines - pharmacology; BRD2; DESIGN; ORTHOSTERIC MODULATION; RECOGNITION; RVX-208; FOCUSED CHEMICAL LIBRARIES; BINDING
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01708

A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4­(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure-based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes.