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Design, synthesis and biological evaluation of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD9 inhibitors.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-02-21 , DOI: 10.1016/j.bmc.2019.02.045 Peiyuan Zheng 1 , Jian Zhang 1 , Hui Ma 1 , Xinrui Yuan 1 , Pan Chen 2 , Jinpei Zhou 2 , Huibin Zhang 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-02-21 , DOI: 10.1016/j.bmc.2019.02.045 Peiyuan Zheng 1 , Jian Zhang 1 , Hui Ma 1 , Xinrui Yuan 1 , Pan Chen 2 , Jinpei Zhou 2 , Huibin Zhang 1
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BRD9 is the subunit of mammalian SWI/SNF chromatin remodeling complex (BAF). SWI/SNF complex mutations were found in nearly 20% of human cancers. The biological role played by BRD9 bromodomain remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. In this paper, we synthesized a series of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD9 inhibitors and evaluated their BRD9 inhibitory activity in vitro and anti-proliferation effects against tumor cells. Gratifyingly, compound 27 and 29 exhibited robust potency of BRD9 inhibition with IC50 values of 35 and 103 nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 27 potently inhibited cell proliferation in cell lines A549 and EOL-1 with an IC50 value of 6.12 μM and 1.76 μM respectively. The chemical probe, compound 27, was identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.
中文翻译：
咪唑并[1,5-a]吡嗪-8（7H）-one衍生物作为BRD9抑制剂的设计，合成和生物学评价。
BRD9是哺乳动物SWI / SNF染色质重塑复合物（BAF）的亚基。在近20％的人类癌症中发现了SWI / SNF复合体突变。BRD9溴结构域发挥的生物学作用仍然知之甚少，因此必须确定有效且高度选择性的抑制剂以有效探索单个溴结构域蛋白的生物学特性。在本文中，我们合成了一系列咪唑并[1,5-a]吡嗪-8（7H）-one衍生物作为有效的BRD9抑制剂，并评估了其对体外BRD9的抑制活性以及对肿瘤细胞的抗增殖作用。令人欣慰的是，化合物27和29表现出强大的BRD9抑制能力，IC50值分别为35和103 nM。进行了对接研究以解释结构-活性关系。此外，化合物27有效抑制细胞系A549和EOL-1中的细胞增殖，IC50值分别为6.12μM和1.76μM。确定了化学探针化合物27，该探针在体外和体内环境中应被证明可用于进一步探索BRD9溴结构域生物学。
更新日期：2019-02-21
中文翻译：
咪唑并[1,5-a]吡嗪-8（7H）-one衍生物作为BRD9抑制剂的设计，合成和生物学评价。
BRD9是哺乳动物SWI / SNF染色质重塑复合物（BAF）的亚基。在近20％的人类癌症中发现了SWI / SNF复合体突变。BRD9溴结构域发挥的生物学作用仍然知之甚少，因此必须确定有效且高度选择性的抑制剂以有效探索单个溴结构域蛋白的生物学特性。在本文中，我们合成了一系列咪唑并[1,5-a]吡嗪-8（7H）-one衍生物作为有效的BRD9抑制剂，并评估了其对体外BRD9的抑制活性以及对肿瘤细胞的抗增殖作用。令人欣慰的是，化合物27和29表现出强大的BRD9抑制能力，IC50值分别为35和103 nM。进行了对接研究以解释结构-活性关系。此外，化合物27有效抑制细胞系A549和EOL-1中的细胞增殖，IC50值分别为6.12μM和1.76μM。确定了化学探针化合物27，该探针在体外和体内环境中应被证明可用于进一步探索BRD9溴结构域生物学。
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