5n49
BRPF2 in complex with Compound 7
Structural highlights
FunctionBRD1_HUMAN Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity.[1] [2] Publication Abstract from PubMedBromodomains (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. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.,Bouche L, Christ CD, Siegel S, Fernandez-Montalvan AE, Holton SJ, Fedorov O, Ter Laak A, Sugawara T, Stockigt D, Tallant C, Bennett J, Monteiro O, Diaz-Saez L, Siejka P, Meier J, Putter V, Weiske J, Muller S, Huber KVM, Hartung IV, Haendler B J Med Chem. 2017 May 1. doi: 10.1021/acs.jmedchem.7b00306. PMID:28402630[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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