RVX-297- a novel BD2 selective inhibitor of BET bromodomains.
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.
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada. Electronic address: olesya@zenithepigenetics.com.
Olesya A
OA
Kharenko
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Emily M
EM
Gesner
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Reena G
RG
Patel
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Karen
K
Norek
Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
Andre
A
White
Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
Eric
E
Fontano
Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
Robert K
RK
Suto
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Peter R
PR
Young
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Kevin G
KG
McLure
Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary, Alberta, T3E 6L1, Canada.
Henrik C
HC
Hansen
D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D052999:Quinazolinones / Q000494:pharmacology*; D013816:Thermodynamics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry
D052999:Quinazolinones; C000619515:RVX-297; D014157:Transcription Factors
BD1 and BD2 domains; BET inhibitors; Bromodomains; Crystal structure; RVX-297; Selectivity