title: Inhibition of hypoxia-inducible transcription factor complex with designed epipolythiodiketopiperazine.
abstract: Designed small molecule inhibitors of hypoxia-inducible gene expression have potential to become new research tools for molecular biology, genetics and serve as leads to new therapeutics. We report design, synthesis evaluation of biological activity, and a preliminary mechanistic study of epipolythiodiketopiperazine (ETP) transcriptional antagonist that targets the interaction between the C-terminal transactivation domain (C-TAD) of hypoxia-inducible factor 1α (HIF-1α) and cysteine-histidine rich region (CH1) of transcriptional coactivator p300/CBP. Our results indicate that in cultured cells synthetic ETP 3 disrupts the structure and function of this complex in a dose-dependent manner, resulting in rapid downregulation of hypoxia-inducible gene expression.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Kushal
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Csaba F
authors.initials: CF
authors.lastname: László
authors.forename: Lajos Z
authors.initials: LZ
authors.lastname: Szábo
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; C555444:epipolythiodiketopiperazine