title: Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit.
abstract: A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play critical roles in cancer maintenance, many of which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe the identification of a small molecule named Targapremir-210 that binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L), a hypoxia-associated protein negatively regulated by miR-210, decreases HIF-1α, and triggers apoptosis of triple negative breast cancer cells only under hypoxic conditions. Further, Targapremir-210 inhibits tumorigenesis in a mouse xenograft model of hypoxic triple negative breast cancer. Many factors govern molecular recognition of biological targets by small molecules. For protein, chemoproteomics and activity-based protein profiling are invaluable tools to study small molecule target engagement and selectivity in cells. Such approaches are lacking for RNA, leaving a void in the understanding of its druggability. We applied Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP) to study the cellular selectivity and the on- and off-targets of Targapremir-210. Targapremir-210 selectively recognizes the miR-210 precursor and can differentially recognize RNAs in cells that have the same target motif but have different expression levels, revealing this important feature for selectively drugging RNAs for the first time. These studies show that small molecules can be rapidly designed to selectively target RNAs and affect cellular responses to environmental conditions, resulting in favorable benefits against cancer. Further, they help define rules for identifying druggable targets in the transcriptome.
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Costales
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Haga
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Sai Pradeep
authors.initials: SP
authors.lastname: Velagapudi
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs-Disney
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.affiliation: Department of Chemistry, ‡Department of Molecular Therapeutics, and §Department of Neuroscience, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Matthew D
authors.identifier: 0000-0001-8486-1796
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D054852:Small Molecule Libraries; C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase