Publication

Article Metrics

Citations


Online attention

Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains

DOI: 10.1021/acs.jmedchem.7b00306 DOI Help

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)