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Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains

DOI: 10.1021/ja412434f DOI Help

Authors: Duncan A. Hay (Department of Chemistry, University of Oxford, U.K.) , Oleg Fedorov (Structural Genomics Consortium, University of Oxford, U.K.) , Sarah Martin (Structural Genomics Consortium, University of Oxford, U.K.) , Dean C. Singleton (Structural Genomics Consortium, University of Oxford, U.K.) , Cynthia Tallant Blanco (Structural Genomics Consortium, University of Oxford, U.K.) , Christopher Wells (Structural Genomics Consortium, University of Oxford, U.K.) , Sarah Picaud (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Martin Philpott (Structural Genomics Consortium, University of Oxford, U.K.) , Octovia P. Monteiro (Structural Genomics Consortium, University of Oxford, U.K.) , Catherine M. Rogers (Structural Genomics Consortium, University of Oxford, U.K.) , Stuart J. Conway (Department of Chemistry, University of Oxford, U.K.) , Timothy P. C. Rooney (Department of Chemistry, University of Oxford, U.K.) , Anthony Tumber (Structural Genomics Consortium, University of Oxford, U.K.) , Clarence Yapp (Structural Genomics Consortium, University of Oxford, U.K.) , Panagis Filippakopoulos (Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, U.K.) , Mark E. Bunnage (Worldwide Medicinal Chemistry, Pfizer, USA.) , Susanne Müller (Structural Genomics Consortium, University of Oxford, U.K.) , S Knapp (Structural Genomics Consortium, University of Oxford) , Christopher J. Schofield (Department of Chemistry, University of Oxford, U.K.) , Paul E. Brennan (Structural Genomics Consortium, University of Oxford, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of The American Chemical Society , VOL 136 (26) , PAGES 9308 - 9319

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

Open Access Open Access

Abstract: Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography