title: Design of a small molecule against an oncogenic noncoding RNA.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Sai Pradeep
authors.initials: SP
authors.lastname: Velagapudi
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Haga
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rosenberg
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Marie
authors.initials: M
authors.lastname: Lafitte
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458 disney@scripps.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000070416:Antagomirs / Q000493:pharmacokinetics / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000493:pharmacokinetics / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070416:Antagomirs; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; D054852:Small Molecule Libraries; C517918:DROSHA protein, human; D043244:Ribonuclease III
keywords: RNA; chemistry; drug design; noncoding RNA; nucleic acids