Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine.
Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of a dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1alpha. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.
Block
Katherine M
KM
Department of Chemistry and Biochemistry, The University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, USA.
Wang
Hui
H
Szabó
Lajos Z
LZ
Polaske
Nathan W
NW
Henchey
Laura K
LK
Dubey
Ramin
R
Kushal
Swati
S
László
Csaba F
CF
Makhoul
Joshua
J
Song
Zuohe
Z
Meuillet
Emmanuelle J
EJ
Olenyuk
Bogdan Z
BZ
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001667:Binding, Competitive; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D054659:Diketopiperazines; D004220:Disulfides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; D050880:p300-CBP Transcription Factors