title: Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.
abstract: Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1).
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Duffy
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Martin
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Ming Min
authors.initials: MM
authors.lastname: Hsia
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: He
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ellis
authors.affiliation: JFQuinn Consulting, 113 Jay St., Albany, NY 12210, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Olesya A
authors.initials: OA
authors.lastname: Kharenko
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Norek
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Gesner
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Young
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: McLure
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Wagner
authors.affiliation: Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
authors.forename: Damodharan
authors.initials: D
authors.lastname: Lakshminarasimhan
authors.affiliation: Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: White
authors.affiliation: Xtal BioStructures, Inc., 12 Michigan Dr., Natick, MA 01760, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Suto
authors.affiliation: Zenith Epigenetics Corp., Suite 300, 4820 Richard Road SW, Calgary, Alberta T3E 6L1, Canada.
authors.forename: Henrik C
authors.initials: HC
authors.lastname: Hansen
authors.affiliation: Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA. Electronic address: douglas.kitchen@amriglobal.com.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kitchen
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; D009687:Nuclear Proteins; D011810:Quinoxalines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD4(1); Bromodomain inhibitors; Hit triage; Protein-ligand docking; Virtual screening