Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains. Bouché, L., Christ, C., D., Siegel, S., Fernández-Montalván, A., E., Holton, S., J., 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, K., V., Hartung, I., V., & Haendler, B. Journal of Medicinal Chemistry, 2017. abstract bibtex 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.
@article{
title = {Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains},
type = {article},
year = {2017},
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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.},
bibtype = {article},
author = {Bouché, Léa and Christ, Clara D. and Siegel, Stephan and Fernández-Montalván, Amaury E. and Holton, Simon J. and Fedorov, Oleg and Ter Laak, Antonius and Sugawara, Tatsuo and Stöckigt, Detlef and Tallant, Cynthia and Bennett, James and Monteiro, Octovia and Díaz-Sáez, Laura and Siejka, Paulina and Meier, Julia and Pütter, Vera and Weiske, Jörg and Müller, Susanne and Huber, Kilian V.M. and Hartung, Ingo V. and Haendler, Bernard},
journal = {Journal of Medicinal Chemistry}
}
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