Pharmacological Targeting of CDK9 in Cardiac Hypertrophy
Pharmacological Targeting of CDK9 in Cardiac Hypertrophy
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DOI：
10.1002/med.20172
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发表时间：
2010-07-01
影响因子：
13.3
通讯作者：
Kohoutek, Jiri
中科院分区：
文献类型：
--
作者：
Krystof, Vladimir;Chamrad, Ivo;Kohoutek, Jiri
心脏肥大使心脏能够适应工作负荷。但持续性或非生理性刺激可导致泵衰竭。心脏肥大的特征是分化的心肌细胞的大小增加。（picas与密集的转录和翻译有关几种细胞周期蛋白依赖性激酶（CDK）已被鉴定为转录的主要调节因子，其中CDK 9与心肌肥大直接相关，CDK 9磷酸化C-RNA聚合酶II的末端结构域，从而刺激转录的延伸期。由于分子肿瘤学家和药物化学家对CDK作为抗癌药物的潜在靶点的长期兴趣，一个小的投资组合-CDK 9的分子抑制剂是可用的最近确定的CDK 9的晶体结构现在允许选择性抑制剂的开发和它们在生化效力和选择性方面的进一步优化CDK 9因此可以构成抗心脏肥大药物的新靶点（c）2009 Wiley Periodicals lire Med Res Rev. 30 No 4，646-666 2010
Cardiac hypertrophy allows the heart to adapt to workload. hut persistent or unphysiological stimulus can result in pump failure Cardiac hypertrophy is characterized by an increase in the size of differentiated cardiac myocytes At the molecular level, growth (picas is linked to intensive transcription and translation Several cyclin-dependent kinases (CDKs) have been identified as principal regulators of transcription, and among these CDK9 is directly associated with cardiac hypertrophy CDK9 phosphorylates the C-terminal domain of RNA polymerase II and thus stimulates the elongation phase of transcription Chronic activation of CDK9 causes not only cardiac myocyte enlargement but also confers predisposition to heart failure Due to the long interest of molecular oncologists and medicinal chemists in CDKs as potential targets of anticancer drugs, a portfolio of small-molecule inhibitors of CDK9 is available Recent determination of CDK9's crystal structure now allows the development of selective inhibitors and their further optimization in terms of biochemical potency and selectivity CDK9 may therefore constitute a novel target for drugs against cardiac hypertrophy (c) 2009 Wiley Periodicals lire Med Res Rev. 30 No 4, 646-666 2010