title: Identification of small molecule Hes1 modulators as potential anticancer chemotherapeutics.
abstract: Hes1 is a key transcriptional regulator primarily controlled by the Notch signaling pathway, and recent studies have demonstrated both an oncogenic and tumor suppressor role for Hes1, depending on the cell type. Small molecules that activate and inhibit Hes1 activity hold promise as future anticancer chemotherapeutics. We have utilized a cell-based dual luciferase assay to identify modulators of Hes1 expression in a medium-throughput format. A modest screen was performed in HCT-116 colon cancer cell lines, and two small molecules were identified and characterized as Hes1 regulators. Compound 3 induced Hes1 expression and exhibited anticancer effects in pulmonary carcinoid tumor cells, a cell type in which the upregulated Notch/Hes1 signaling plays a tumor suppressive role. Treatment of HCT-116 cells with compound 12 resulted in Hes1 downregulation and antitumor effects.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA.
authors.forename: Vibhavari
authors.initials: V
authors.lastname: Sail
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
mesh_terms: D000609:Aminoacridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000072056:Transcription Factor HES-1; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000609:Aminoacridines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D003374:Coumarins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D054852:Small Molecule Libraries; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human