Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics
Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics
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DOI：
10.1021/ml300110s
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Ryckman, David M.
中科院分区：
文献类型：
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作者：
Haddach, Mustapha;Schwaebe, Michael K.;Ryckman, David M.
实体瘤和血液癌细胞的加速增殖与RNA聚合酶I（Pol I）酶加速rDNA转录以产生升高水平的rRNA（rRNA）有关。实际上，Pol I的上调（通常由肿瘤抑制因子和癌基因之间的突变改变引起）是维持癌症表型所需的，并且形成了寻求Pol I的选择性抑制剂作为抗癌治疗剂的基础。2-（4-甲基-[1，4]二氮杂环庚烷-1-基）-5-氧代-5H-7-硫杂-1，11b-二氮杂-苯并[c]芴-6-羧酸（5-甲基-吡嗪-2-基甲基）-酰胺（CX-5461，7 c）已被确定为第一种有效、选择性和口服生物利用的RNA Pot I转录抑制剂，在肿瘤生长有效性模型中具有体内活性。临床前数据支持CX-5461作为一种具有多种类型癌症活性的抗癌药物的开发。
Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pot I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pot I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.