title: LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
abstract: The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactamLP99is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development ofLP99from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover,LP99was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).
authors.forename: Peter G K
authors.initials: PG
authors.lastname: Clark
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).
authors.forename: Lucas C C
authors.initials: LC
authors.lastname: Vieira
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Dean C
authors.initials: DC
authors.lastname: Singleton
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rogers
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Octovia P
authors.initials: OP
authors.lastname: Monteiro
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Roberta
authors.initials: R
authors.lastname: Baronio
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, W153611 (USA).
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, W153611 (USA).
authors.forename: Jacqui
authors.initials: J
authors.lastname: Méndez
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ (UK).
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Dixon
keywords: Bromodomänen; Enantioselektive Katalyse; Epigenetik; Kaskadenreaktionen; Organokatalyse