title: Studies on novel HIF activators, A-503451sII: biological activities of A-503451A.
abstract: In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1α protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin. Addition of excess ferric chloride to the culture medium suppressed the HIF-induction activity of A-503451A. A-503451A did not have iron-chelating activity in vitro, but decreased the intracellular labile iron pool concentration. These data indicate that A-503451A is a unique HIF activator.
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Ohyama
authors.affiliation: Biologics Technology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Kitamura-Miyazaki
authors.affiliation: Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirota-Takahata
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ando
mesh_terms: D003470:Culture Media / Q000737:chemistry; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005285:Fermentation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C000617989:A-503451A; D003470:Culture Media; C554270:EPO protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D007502:Iron Chelating Agents; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin