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

Journal Article · Fri Aug 12 00:00:00 EDT 2016 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2016.06.021· OSTI ID:22606146

Gesner, Emily M.; Patel, Reena G.; Norek, Karen ^[1]; White, Andre; Fontano, Eric; Suto, Robert K. ^[2]; Young, Peter R.; McLure, Kevin G.; Hansen, Henrik C. ^[1]

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1. Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1 (Canada)
2. Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760 (United States)

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. - Highlights: • 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.

• OSTI ID: 22606146
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 477, Issue 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CALORIMETRY
CARDIOVASCULAR DISEASES
CLINICAL TRIALS
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
HISTONES
LYSINE
MOLECULES
THERMODYNAMIC PROPERTIES
THERMODYNAMICS
TITRATION
TRANSCRIPTION
TRANSCRIPTION FACTORS
X RADIATION