A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation- Pi Interaction

DOI: 10.1002/anie.201402750
PMID: 24821300

Authors: Timothy P. C. Rooney (Department of Chemistry, Chemistry Research Laboratory, University of Oxford, U.K.) , Panagis Filippakopoulos (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Oleg Fedorov (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Sarah Picaud (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Wilian A. Cortopassi (Department of Chemistry, Chemistry Research Laboratory, University of Oxford, U.K.) , Duncan A. Hay (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Sarah Martin (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Anthony Tumber (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Catherine M. Rogers (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Martin Philpott (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Minghua Wang (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Amber L. Thompson (Department of Chemistry, Chemistry Research Laboratory, University of Oxford, U.K.) , Tom D. Heightman (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , David C. Pryde (Neusentis, Cambridge, U.K.) , Andrew Cook (Neusentis, Cambridge, U.K.) , Robert S. Paton (Department of Chemistry, Chemistry Research Laboratory, University of Oxford, U.K.) , Susanne Müller (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Stefan Knapp (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Paul E. Brennan (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Stuart J. Conway (Department of Chemistry, Chemistry Research Laboratory, University of Oxford, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 53 (24) , PAGES 6126 - 6130

State: Published (Approved)
Published: June 2014
Diamond Proposal Number(s): 8421

Abstract: The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation–? interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.

Journal Keywords: Bromodomain;Crebbp;Enzyme Inhibitors;Epigenetics;Ligand Discovery

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography