title: Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA.
abstract: RNA drug targets are pervasive in cells, but methods to design small molecules that target them are sparse. Herein, we report a general approach to score the affinity and selectivity of RNA motif-small molecule interactions identified via selection. Named High Throughput Structure-Activity Relationships Through Sequencing (HiT-StARTS), HiT-StARTS is statistical in nature and compares input nucleic acid sequences to selected library members that bind a ligand via high throughput sequencing. The approach allowed facile definition of the fitness landscape of hundreds of thousands of RNA motif-small molecule binding partners. These results were mined against folded RNAs in the human transcriptome and identified an avid interaction between a small molecule and the Dicer nuclease-processing site in the oncogenic microRNA (miR)-18a hairpin precursor, which is a member of the miR-17-92 cluster. Application of the small molecule, Targapremir-18a, to prostate cancer cells inhibited production of miR-18a from the cluster, de-repressed serine/threonine protein kinase 4 protein (STK4), and triggered apoptosis. Profiling the cellular targets of Targapremir-18a via Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP), a covalent small molecule-RNA cellular profiling approach, and other studies showed specific binding of the compound to the miR-18a precursor, revealing broadly applicable factors that govern small molecule drugging of noncoding RNAs.
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, 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, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Tuan
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Hafeez S
authors.initials: HS
authors.lastname: Haniff
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Martinez
authors.affiliation: Department of Chemistry, Informatics Core, and Genomics Core, 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, Informatics Core, and Genomics Core, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney