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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography	Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains Léa Bouché , Clara D. Christ , Stephan Siegel , Amaury E. Fernández-Montalván , Simon J. Holton , Oleg Fedorov , Antonius Ter Laak , Tatsuo Sugawara , Detlef Stöckigt , Cynthia Tallant , James Bennett , Octovia Monteiro , Laura Díaz-Sáez , Paulina Siejka , Julia Meier , Vera Pütter , Jörg Weiske , Susanne Müller , Kilian V. M. Huber , Ingo V. Hartung , Bernard Haendler Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00306 Diamond Proposal Number(s): [15558, 10619] Show Abstract ▼ 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.	May 2017

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I02-Macromolecular Crystallography

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