Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing bothin vitroand in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable.

中文翻译：

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批准的抗癌药物靶向致癌非编码RNA

在整个人类转录组中都发现了小分子的潜在RNA药物靶标，但是已知通过直接靶向RNA引起药理反应的小分子仅限于抗菌剂。在本文中，我们描述了AbsorbArray，这是一种基于小分子微阵列的方法，允许以未经修饰的化合物（包括FDA批准的药物）以大规模平行形式与RNA基序文库结合进行探测。几种药物结合RNA，包括激酶和拓扑异构酶抑制剂。后者与致癌microRNA（miR）-21的Dicer位点中发现的基序紧密结合，并在体外和细胞中均抑制了其加工。最有效的化合物可抑制下游蛋白质靶标并抑制miR-21介导的侵袭性表型。该化合物的活性在pre-miR-21过表达时被消除。