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2016年5月11日，美国国家科学院院刊（PNAS）在线发表了斯克里普斯研究所（TSRI）的突破性研究成果，成功设计了一种靶向致癌非编码核糖核酸（RNA）的小分子药物，首次成功在动物模型中抑制了三阴乳腺癌的生长。三阴乳腺癌是乳腺癌中最凶险也最难治疗的一种，大约占乳腺癌的16%。 值得注意的是，该药物特异性很高，只杀死表达致癌RNA的癌细胞，对健康细胞无影响。该研究是精准医疗的又一个突破。 用特异性药物作用于致病分子是精准医疗的主要目标。不过，设计这样的药物需要进行大量筛选，耗时长成本高。该研究展示了一个强大的药物设计工具——Inforna。该算法可以帮助人们设计与RNA（尤其是微RNA）结合的化合物。 微RNA（microRNA，miRNA，miR）是长约22nt的非编码RNA，在胚胎发育、细胞分化和器官生成等重要过程中承担着关键性的调控功能。这些短RNA在天然细胞中大量存在，能与靶基因的mRNA配对并阻碍其翻译，在转录后水平上调控目标基因的表达。许多微RNA都与人类疾病有关，比如微RNA-96会阻止细胞程序化死亡，由此促进癌细胞的生长。 该研究以微RNA-96为靶标设计了药物Targaprimir-96，可促使乳腺癌细胞“自杀”。该研究用Targaprimir-96对三阴乳腺癌动物模型进行了为期21天的治疗。实验结果证实，Targaprimir-96能够减少微RNA-96的产量，增强细胞程序化死亡，显著抑制肿瘤的生长。 Proc Natl Acad Sci U S A. 2016 May 11. [Epub ahead of print] Design of a small molecule against an oncogenic noncoding RNA. Sai Pradeep Velagapudi, Michael D. Cameron, Christopher L. Haga, Laura H. Rosenberg, Marie Lafitte, Derek R. Duckett, Donald G. Phinney, Matthew D. Disneya. The Scripps Research Institute, Jupiter, FL 33458, USA. Significance The goal of precision medicine is to identify selective drugs that modulate disease-causing biomolecules. This slow process often involves developing a high-throughput screen to test millions of potential drugs to find a few that affect the biomolecule. Here, we describe a facile approach using a disease-causing biomolecule's sequence to enable design of specific drugs, eliminating arduous and time-consuming screens. By using the sequence of a non-protein-coding, oncogenic RNA, we designed a drug specifically targeting the RNA's folded structure. In cells and animals, the drug inhibits its target, killing cancer cells while leaving healthy cells unaffected. Thus, a preclinical anticancer drug candidate can be quickly designed from sequence. Abstract The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm. DOI: 10.1073/pnas.1523975113 |
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