Inhibition of hypoxia-inducible transcription factor complex with designed epipolythiodiketopiperazine.
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.
Kushal
Swati
S
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA.
Wang
Hui
H
László
Csaba F
CF
Szábo
Lajos Z
LZ
Olenyuk
Bogdan Z
BZ
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*
D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; C555444:epipolythiodiketopiperazine