RVX-297- a novel BD2 selective inhibitor of BET bromodomains

• Published in: Biochemical and biophysical research communications Vol. 477; no. 1; pp. 62 - 67
• Main Authors: Kharenko, Olesya A., Gesner, Emily M., Patel, Reena G., Norek, Karen, White, Andre, Fontano, Eric, Suto, Robert K., Young, Peter R., McLure, Kevin G., Hansen, Henrik C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.08.2016
• Subjects: 60 APPLIED LIFE SCIENCES; BD1 and BD2 domains; BET; BET inhibitors; binding properties; Binding Sites; BRD; Bromodomains; CALORIMETRY; CARDIOVASCULAR DISEASES; CLINICAL TRIALS; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; Crystallography, X-Ray; epigenetics; HISTONES; ITC; LYSINE; MOLECULES; pharmacokinetics; Quinazolinones - pharmacology; RVX-297; Selectivity; THERMODYNAMIC PROPERTIES; THERMODYNAMICS; TITRATION; TRANSCRIPTION; TRANSCRIPTION FACTORS; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; X RADIATION; X-ray diffraction; BET; BD1 and BD2 domains; BRD; Bromodomains; ITC; Selectivity; RVX-297; BET inhibitors; Crystal structure
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.06.021

Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains. [Display omitted] •A novel inhibitor of BET bromodomains, RVX-297 is described.•The differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography are described.•RVX-297 preferentially binds to the BD2 domains of the BET bromodomains.•The structural and thermodynamic properties of the BD2 selective binding of RVX-297 are characterized.