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Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-10 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00611 Niall Igoe 1 , Elliott D. Bayle 1 , Cynthia Tallant 2 , Oleg Fedorov 2 , Julia C. Meier 2 , Pavel Savitsky 2 , Catherine Rogers 2 , Yannick Morias 3 , Sarah Scholze 3 , Helen Boyd 3 , Danen Cunoosamy 3 , David M. Andrews 4 , Anne Cheasty 5 , Paul E. Brennan 2 , Susanne Müller 2, 6 , Stefan Knapp 2, 6, 7 , Paul V. Fish 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-10 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00611 Niall Igoe 1 , Elliott D. Bayle 1 , Cynthia Tallant 2 , Oleg Fedorov 2 , Julia C. Meier 2 , Pavel Savitsky 2 , Catherine Rogers 2 , Yannick Morias 3 , Sarah Scholze 3 , Helen Boyd 3 , Danen Cunoosamy 3 , David M. Andrews 4 , Anne Cheasty 5 , Paul E. Brennan 2 , Susanne Müller 2, 6 , Stefan Knapp 2, 6, 7 , Paul V. Fish 1
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The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability
中文翻译：
溴结构域和植物同源域指状蛋白（BRPF）家族的化学探针的设计
含溴结构域和植物同源结构域的手指（BRPF）家族是支架蛋白，对于将MYST家族的组蛋白乙酰基转移酶募集到染色质中非常重要。在这里，我们将NI-57（16）描述为BRPF的溴结构域（BRD）的新pan-BRPF化学探针。与BRPF3相比，抑制剂16优先结合BRPF1和BRPF2的BRD，而与BRD9的结合较弱。化合物16对非IV类BRD蛋白具有出色的选择性。在nanoBRET和FRAP分析中证明了BRPF1B和BRPF2与16的靶标结合。绑定16通过X射线共晶结构确定，对BRPF1B的合成进行了合理化，与以前的结构相比，该结构显示出翻转的结合方向。我们报告的研究表明16在癌症和炎症模型中通过在低微摩尔浓度下调节表型在细胞测定中具有功能活性。在小鼠中单剂给药产生了16种药代动力学数据，显示出良好的口服生物利用度
更新日期：2017-08-10
中文翻译：
溴结构域和植物同源域指状蛋白（BRPF）家族的化学探针的设计
含溴结构域和植物同源结构域的手指（BRPF）家族是支架蛋白，对于将MYST家族的组蛋白乙酰基转移酶募集到染色质中非常重要。在这里，我们将NI-57（16）描述为BRPF的溴结构域（BRD）的新pan-BRPF化学探针。与BRPF3相比，抑制剂16优先结合BRPF1和BRPF2的BRD，而与BRD9的结合较弱。化合物16对非IV类BRD蛋白具有出色的选择性。在nanoBRET和FRAP分析中证明了BRPF1B和BRPF2与16的靶标结合。绑定16通过X射线共晶结构确定，对BRPF1B的合成进行了合理化，与以前的结构相比，该结构显示出翻转的结合方向。我们报告的研究表明16在癌症和炎症模型中通过在低微摩尔浓度下调节表型在细胞测定中具有功能活性。在小鼠中单剂给药产生了16种药代动力学数据，显示出良好的口服生物利用度
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