title: 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain.
abstract: The 2-amine-9H-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of the lead compound 11 to the bromodomain of BRD9 results in an unprecedented rearrangement of residues forming the acetyllysine recognition site, affecting plasticity of the protein in an induced-fit pocket. The compound does not exhibit any cytotoxic effect in HEK293 cells and displaces the BRD9 bromodomain from chromatin in bioluminescence proximity assays without affecting the BRD4/histone complex. The 2-amine-9H-purine scaffold represents a novel template that can be further modified to yield highly potent and selective tool compounds to interrogate the biological role of BRD9 in diverse cellular systems.
authors.affiliation: †Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Strocchia
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.affiliation: §Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Mendez
authors.affiliation: §Promega Corporation, 2800 Woods Hollow Road, Madison, Wisconsin 53711, United States.
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.affiliation: ‡Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
authors.affiliation: †Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|∥Nuffield Department of Clinical Medicine, Ludwig Cancer Research, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
mesh_terms: D000586:Amination; D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D002843:Chromatin; D006657:Histones; D011687:Purines; D014157:Transcription Factors; C587454:BRD9 protein, human; D000092468:Bromodomain Containing Proteins; C030985:purine