title: Discovery of inhibitors of aberrant gene transcription from Libraries of DNA binding molecules: inhibition of LEF-1-mediated gene transcription and oncogenic transformation.
abstract: The screening of a >9000 compound library of synthetic DNA binding molecules for selective binding to the consensus sequence of the transcription factor LEF-1 followed by assessment of the candidate compounds in a series of assays that characterized functional activity (disruption of DNA-LEF-1 binding) at the intended target and site (inhibition of intracellular LEF-1-mediated gene transcription) resulting in a desired phenotypic cellular change (inhibit LEF-1-driven cell transformation) provided two lead compounds: lefmycin-1 and lefmycin-2. The sequence of screens defining the approach assures that activity in the final functional assay may be directly related to the inhibition of gene transcription and DNA binding properties of the identified molecules. Central to the implementation of this generalized approach to the discovery of DNA binding small molecule inhibitors of gene transcription was (1) the use of a technically nondemanding fluorescent intercalator displacement (FID) assay for initial assessment of the DNA binding affinity and selectivity of a library of compounds for any sequence of interest, and (2) the technology used to prepare a sufficiently large library of DNA binding compounds.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, usa.
authors.forename: James S
authors.initials: JS
authors.lastname: Stover
authors.forename: Jin
authors.initials: J
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002645:Chickens; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D057166:High-Throughput Screening Assays; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D054852:Small Molecule Libraries; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
chemical_list: D051821:Lymphoid Enhancer-Binding Factor 1; D054852:Small Molecule Libraries; D004247:DNA