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Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-01 , DOI: 10.1021/acs.jmedchem.7b00306 Léa Bouché 1 , Clara D Christ 1 , Stephan Siegel 1 , Amaury E Fernández-Montalván 1 , Simon J Holton 1 , Oleg Fedorov 2, 3 , Antonius Ter Laak 1 , Tatsuo Sugawara 1 , Detlef Stöckigt 1 , Cynthia Tallant 2, 3 , James Bennett 2, 3 , Octovia Monteiro 2, 3 , Laura Díaz-Sáez 2, 3 , Paulina Siejka 2, 3 , Julia Meier 2 , Vera Pütter 1 , Jörg Weiske 1 , Susanne Müller 2, 3 , Kilian V M Huber 2, 3 , Ingo V Hartung 1 , Bernard Haendler 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-01 , DOI: 10.1021/acs.jmedchem.7b00306 Léa Bouché 1 , Clara D Christ 1 , Stephan Siegel 1 , Amaury E Fernández-Montalván 1 , Simon J Holton 1 , Oleg Fedorov 2, 3 , Antonius Ter Laak 1 , Tatsuo Sugawara 1 , Detlef Stöckigt 1 , Cynthia Tallant 2, 3 , James Bennett 2, 3 , Octovia Monteiro 2, 3 , Laura Díaz-Sáez 2, 3 , Paulina Siejka 2, 3 , Julia Meier 2 , Vera Pütter 1 , Jörg Weiske 1 , Susanne Müller 2, 3 , Kilian V M Huber 2, 3 , Ingo V Hartung 1 , Bernard Haendler 1
Affiliation
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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.
中文翻译：
苯并异喹啉二酮作为BRPF2和TAF1 / TAF1L溴结构域的有效抑制剂和选择性抑制剂。
溴结构域（BD）是存在于许多与染色质相关的蛋白质中的赖氨酸乙酰化标记的阅读器。在这里，我们描述了溴结构域和PHD手指（BRPF）家族成员BRPF2和TATA盒结合蛋白相关因子TAF1和TAF1L的双重抑制剂。这些蛋白质存在于大型染色质复合物中，并在转录调控中起重要作用。通过高通量筛选鉴定了取代的苯并异喹啉二酮系列，并且随后的结构-活性关系优化允许生成具有对BRPF1和BRPF3 BDs的强选择性的低纳摩尔BRPF2 BD抑制剂。另外，对于大多数衍生物，对TAF1 / TAF1L BD2的抑制作用也很强。该系列中最好的化合物是BAY-299，它是一种非常有效的双重抑制剂，对BRPF2 BD的IC50为67 nM，TAF1 BD2为8 nM，TAF1L BD2为106 nM。重要的是，没有测量BRD4 BDs的活性。此外，使用BRPF2-或TAF1-组蛋白H3.3或H4相互作用测定可证明细胞活性。
更新日期：2017-05-01
中文翻译：
苯并异喹啉二酮作为BRPF2和TAF1 / TAF1L溴结构域的有效抑制剂和选择性抑制剂。
溴结构域（BD）是存在于许多与染色质相关的蛋白质中的赖氨酸乙酰化标记的阅读器。在这里，我们描述了溴结构域和PHD手指（BRPF）家族成员BRPF2和TATA盒结合蛋白相关因子TAF1和TAF1L的双重抑制剂。这些蛋白质存在于大型染色质复合物中，并在转录调控中起重要作用。通过高通量筛选鉴定了取代的苯并异喹啉二酮系列，并且随后的结构-活性关系优化允许生成具有对BRPF1和BRPF3 BDs的强选择性的低纳摩尔BRPF2 BD抑制剂。另外，对于大多数衍生物，对TAF1 / TAF1L BD2的抑制作用也很强。该系列中最好的化合物是BAY-299，它是一种非常有效的双重抑制剂，对BRPF2 BD的IC50为67 nM，TAF1 BD2为8 nM，TAF1L BD2为106 nM。重要的是，没有测量BRD4 BDs的活性。此外，使用BRPF2-或TAF1-组蛋白H3.3或H4相互作用测定可证明细胞活性。
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