Inhibition of VEGF transcription through blockade of the hypoxia inducible factor-1α-p300 interaction by a small molecule.
Vascular endothelial growth factor (VEGF) plays a pro-angiogenic role in tumor progression. Stabilization of a key regulator termed the hypoxia inducible factor (HIF)-1α under oxygen deficient environment around tumor is known to elicit expression of VEGF through binding to p300. Thus, inhibition of the HIF-1α-p300 interaction would lead to down-regulation of VEGF expression, thereby providing potential cancer therapeutics. Here, we have screened a chemical library against the interaction of the HIF-1α-derived peptide with p300 employing a fluorescence polarization-based assay. We have identified a compound as the most prominent inhibitor against the protein-protein interaction. Further, we have observed suppression of the mRNA level of VEGF upon treatment of HeLa cells with the compound, demonstrating its inhibitory effect at the cellular level.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Hyuk Sung
HS
Kwon
Da-Rae
DR
Kim
Eun Gyeong
EG
Yang
Yong Keun
YK
Park
Hee-Chul
HC
Ahn
Sun-Joon
SJ
Min
Dae-Ro
DR
Ahn
D002470:Cell Survival / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005454:Fluorescence Polarization; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human