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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 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_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Bouché L,Christ CD,Siegel S,Fernández-Montalván AE,Holton SJ,Fedorov O,Ter Laak A,Sugawara T,Stöckigt D,Tallant C,Bennett J,Monteiro O,Díaz-Sáez L,Siejka P,Meier J,Pütter V,Weiske J,Müller S,Huber KVM,Hartung IV,H

doi

10.1021/acs.jmedchem.7b00306

subject

Has Abstract

pub_date

2017-05-11 00:00:00

pages

4002-4022

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

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