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Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains
DOI:
10.1021/acs.jmedchem.7b00306
Authors:
Léa
Bouché
(Bayer AG)
,
Clara D.
Christ
(Bayer AG)
,
Stephan
Siegel
(Bayer AG)
,
Amaury E.
Fernández-Montalván
(Bayer AG)
,
Simon J.
Holton
(Bayer AG)
,
Oleg
Fedorov
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Antonius
Ter Laak
(Bayer AG)
,
Tatsuo
Sugawara
(Bayer AG)
,
Detlef
Stöckigt
(Bayer AG)
,
Cynthia
Tallant
(Structural Genomics Consortium, University of Oxford)
,
James
Bennett
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Octovia
Monteiro
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Laura
Díaz-Sáez
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Paulina
Siejka
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Julia
Meier
(Structural Genomics Consortium, University of Oxford)
,
Vera
Pütter
(Bayer AG)
,
Jörg
Weiske
(Bayer AG)
,
Susanne
Müller
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Kilian V. M.
Huber
(Structural Genomics Consortium, University of Oxford; Target Discovery Institute)
,
Ingo V.
Hartung
(Bayer AG)
,
Bernard
Haendler
(Bayer AG)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
State:
Published (Approved)
Published:
May 2017
Diamond Proposal Number(s):
15558
,
10619
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 IC50 of 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.
Journal Keywords: Anatomy; Assays; Rodent models; Inhibitors; Selectivity
Subject Areas:
Biology and Bio-materials,
Medicine,
Chemistry
Instruments:
I02-Macromolecular Crystallography
Added On:
03/05/2017 11:19
Documents:
acs.jmedchem.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)