title: Modulation of alternative splicing with chemical compounds in new therapeutics for human diseases.
abstract: Alternative splicing is a critical step where a limited number of human genes generate a complex and diverse proteome. Various diseases, including inherited diseases with abnormalities in the "genome code," have been found to result in an aberrant mis-spliced "transcript code" with correlation to the resulting phenotype. Chemical compound-based and nucleic acid-based strategies are trying to target this mis-spliced "transcript code". We will briefly mention about how to obtain splicing-modifying-compounds by high-throughput screening and overview of what is known about compounds that modify splicing pathways. The main focus will be on RNA-binding protein kinase inhibitors. In the main text, we will refer to diseases where splicing-modifying-compounds have been intensively investigated, with comparison to nucleic acid-based strategies. The information on their involvement in mis-splicing as well as nonsplicing events will be helpful in finding better compounds with less off-target effects for future implications in mis-splicing therapy.
authors.affiliation: †Department of Anatomy and Developmental Biology and ‡Training Program of Leaders for Integrated Medical System for Fruitful Healthy-Longevity Society (LIMS), Kyoto University Graduate School of Medicine, Kyoto 606-8315, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohe
authors.affiliation: †Department of Anatomy and Developmental Biology and ‡Training Program of Leaders for Integrated Medical System for Fruitful Healthy-Longevity Society (LIMS), Kyoto University Graduate School of Medicine, Kyoto 606-8315, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D003583:Cytokinins / Q000494:pharmacology; D004314:Down Syndrome / Q000188:drug therapy; D004402:Dysautonomia, Familial / Q000188:drug therapy / Q000503:physiopathology; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D058990:Molecular Targeted Therapy / Q000379:methods*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors; D000097603:Dyrk Kinases
chemical_list: D003583:Cytokinins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; D000097603:Dyrk Kinases; C112491:SF3B1 protein, human; C066780:Clk dual-specificity kinases