title: Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.
abstract: Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Léa
authors.identifier: 0000-0001-8523-812X
authors.initials: L
authors.lastname: Bouché
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Christ
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Siegel
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Amaury E
authors.initials: AE
authors.lastname: Fernández-Montalván
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Holton
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Antonius
authors.initials: A
authors.lastname: Ter Laak
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sugawara
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Stöckigt
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Bennett
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Octovia
authors.initials: O
authors.lastname: Monteiro
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Laura
authors.initials: L
authors.lastname: Díaz-Sáez
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Paulina
authors.initials: P
authors.lastname: Siejka
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Julia
authors.initials: J
authors.lastname: Meier
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Pütter
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Weiske
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford , Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Kilian V M
authors.identifier: 0000-0002-1103-5300
authors.initials: KVM
authors.lastname: Huber
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Ingo V
authors.initials: IV
authors.lastname: Hartung
authors.affiliation: Drug Discovery, Bayer AG , Müllerstrasse 178, 13353 Berlin, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Haendler
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D056488:Histone Chaperones; D006801:Humans; D007536:Isomerism; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D035381:TATA-Binding Protein Associated Factors / Q000037:antagonists & inhibitors*; D035362:Transcription Factor TFIID / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D007546:Isoquinolines; D009687:Nuclear Proteins; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C472868:TAF1L protein, human; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins; C069001:TATA-binding protein associated factor 250 kDa