Small molecule inhibition of microRNA-21 expression reduces cell viability and microtumor formation
作者:Nicholas Ankenbruck、Rohan Kumbhare、Yuta Naro、Meryl Thomas、Laura Gardner、Cole Emanuelson、Alexander Deiters
DOI:10.1016/j.bmc.2019.05.044
日期:2019.8
one of the most established oncogenic miRNAs, is found to be upregulated in a wide range of cancers making it an attractive therapeutic target. Employment of a luciferase-based live-cell reporter assay in a high-throughput screen of >300,000 small molecules led to the discovery of a new class of ether-amide miR-21 inhibitors. Following a structure-activity relationship study, an optimized lead molecule
MicroRNA(miRNA)是短的非编码RNA分子,估计可调节大量蛋白质编码基因的表达,并与多种生物学过程有关,例如发育,分化,增殖和细胞存活。miRNA的失调归因于各种人类疾病(包括癌症)的发作和发展。发现MicroRNA-21(miR-21)是最成熟的致癌miRNA之一,在多种癌症中均被上调,使其成为有吸引力的治疗靶标。在> 300,000个小分子的高通量筛选中使用基于荧光素酶的活细胞报告基因测定法,导致发现了一类新型的醚酰胺miR-21抑制剂。经过结构-活性关系研究,发现优化的前导分子可抑制miR-21转录。此外,该抑制剂通过诱导凋亡在宫颈癌细胞系中显示出细胞毒性,并且在长期的克隆形成测定中能够减少微肿瘤的形成。总而言之,这项工作报告了一种新的miR-21小分子抑制剂的发现,并证明了其作为癌症治疗替代方法的潜力。