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The “Gatekeeper” Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains

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Department of Chemistry and Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
*E-mail: [email protected]. Phone: +41 44 635 55 21.
*E-mail: [email protected]. Phone: +41 44 635 39 45.
Cite this: J. Med. Chem. 2016, 59, 7, 3087–3097
Publication Date (Web):March 16, 2016
Copyright © 2016 American Chemical Society

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    Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ∼200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01757.

    • General procedures for scaffold hopping, synthesis and characterization, biophysical and biological evaluation of final compounds, and X-ray crystal structure refinement data (PDF)

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    Accession Codes

    The PDB entries for CREBBP and BRPF1b in complex with the hit compound 1b are 4TS8 and 5D7X, respectively. Coordinates and structure factors for the BAZ2B bromodomain in complex with compounds 47 and 50 have been deposited in the PDB as entries 5E73 and 5E74, respectively.

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