Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.
Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.
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DOI：
10.1021/acs.jmedchem.7b00306
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发表时间：
2017-05-11
影响因子：
7.3
通讯作者：
Haendler B
中科院分区：
文献类型：
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作者：
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;Haendler B
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读取器。在这里，我们描述了溴结构域和 PHD 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，在转录调控中发挥重要作用。通过高通量筛选鉴定了取代的苯并异喹啉二酮系列，随后的结构-活性关系优化允许生成对 BRPF1 和 BRPF3 BD 具有强选择性的低纳摩尔 BRPF2 BD 抑制剂。此外，大多数衍生物对 TAF1/TAF1L BD2 都有强烈的抑制作用。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，对 TAF1 BD2 的 IC50 为 8 nM，对 TAF1L BD2 的 IC50 为 106 nM。重要的是，没有测量 BRD4 BD 的活性。此外，使用 BRPF2 或 TAF1 组蛋白 H3.3 或 H4 相互作用测定来证明细胞活性。
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.