title: Discovery of a PCAF Bromodomain Chemical Probe.
abstract: The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.|Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: Moses
authors.identifier: 0000-0002-5006-5684
authors.initials: M
authors.lastname: Moustakim
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, V5A 1S6, Canada.
authors.forename: Peter G K
authors.initials: PG
authors.lastname: Clark
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Trulli
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: Angel L
authors.initials: AL
authors.lastname: Fuentes de Arriba
authors.affiliation: ARUK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Ehebauer
authors.affiliation: Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, 60438, Frankfurt am Main, Germany.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: ARUK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Murphy
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, WI, 153611, USA.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Mendez-Johnson
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, WI, 153611, USA.
authors.forename: Danette
authors.initials: D
authors.lastname: Daniels
authors.affiliation: Structural Genomics Consortium, MaRS South Tower, Suite 732, 101 College Street, Toronto, Ontario, M5G 1LZ, Canada.
authors.forename: Chun-Feng D
authors.initials: CD
authors.lastname: Hou
authors.affiliation: Structural Genomics Consortium, MaRS South Tower, Suite 732, 101 College Street, Toronto, Ontario, M5G 1LZ, Canada.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Structural Genomics Consortium, MaRS South Tower, Suite 732, 101 College Street, Toronto, Ontario, M5G 1LZ, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Structural Genomics Consortium, MaRS South Tower, Suite 732, 101 College Street, Toronto, Ontario, M5G 1LZ, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.affiliation: Nuffield Department of Medicine and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Yang
authors.affiliation: Nuffield Department of Medicine and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Dorrell
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: 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: Kilian V M
authors.initials: KV
authors.lastname: Huber
authors.affiliation: Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, 60438, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: UCB Pharma Ltd, Slough, SL1 3WE, UK.
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
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
authors.affiliation: Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.|ARUK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
authors.forename: Paul E
authors.identifier: 0000-0002-8950-7646
authors.initials: PE
authors.lastname: Brennan
mesh_terms: D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006830:Hydralazine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
chemical_list: D001391:Azo Compounds; D006830:Hydralazine; D015335:Molecular Probes; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: bromodomains; chemical probes; epigenetics; medicinal chemistry; structure-based design