title: Chemical biology of compounds obtained from screening using disease models.
abstract: Bioactive compounds are extremely powerful tools for studying biological systems because they can rapidly, conditionally, often reversibly, and dose-dependently modulate the biological function of living cells. Moreover, they are expected to be drug seeds for chemotherapy of several diseases. Two approaches are used to find and obtain bioactive compounds, namely, molecular-target-based screening and phenotypic screening. Through phenotypic screening that mimics tumor metastasis, multi-drug resistance, and Parkinson's disease, we identified several compounds that inhibit cancer cell migration, anti-apoptotic function of Bcl-2/Bcl-xL, and neuronal cell death. By using MEK inhibitor that was developed by target-based screening, we discovered that MEK inhibitor selectively induces apoptosis in tumor cells with β-catenin mutation. Using target-based screening, we identified arabilin, a novel androgen antagonist. In this review, we introduce our recent studies on the identification of bioactive compounds by phenotypic screening and by target-based screening for drug-seed discovery.
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
authors.forename: Estu
authors.initials: E
authors.lastname: Tashiro
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan. imoto@bio.keio.ac.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases
keywords: Androgen; Apoptosis; Cell migration; MEK; Parkinson’s disease; β-Catenin