PT  - JOURNAL ARTICLE
AU  - Lauzier, Marie-Claude
AU  - Robitaille, Geneviève A.
AU  - Chan, Denise A.
AU  - Giaccia, Amato J.
AU  - Richard, Darren E.
TI  - (2<em>R</em>)-[(4-Biphenylylsulfonyl)amino]-<em>N</em>-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors
AID  - 10.1124/mol.108.045690
DP  - 2008 Jul 01
TA  - Molecular Pharmacology
PG  - 282--288
VI  - 74
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/74/1/282.short
4100  - http://molpharm.aspetjournals.org/content/74/1/282.full
SO  - Mol Pharmacol2008 Jul 01; 74
AB  - Hypoxia-inducible factors (HIFs) are unstable heterodimeric transcription factors and decisive elements for the transcriptional regulation of genes important in the adaptation to low-oxygen conditions. Hypoxia is the ubiquitous inducer of HIFs, stabilizing the α-subunit and permitting the formation of a functional HIF complex. Here, we identify (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a commercially available metalloprotease-2 and -9 inhibitor, as a rapid and potent inducer of HIFs. We show that in different cell lines, BiPS induces the HIF-α subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF-1α hydroxylation. The HIF-1 complex, formed after BiPS treatment, is capable of DNA binding and activation of HIF target genes, including the expression of vascular endothelial growth factor. Because novel HIF activators have generated considerable interest in the possible treatment of different ischemic diseases, we believe that BiPS and derivative molecules could have strong therapeutic potential. The American Society for Pharmacology and Experimental Therapeutics