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(2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors

Centre de recherche de L'Hôtel-Dieu de Québec and the Department of Medicine, Université Laval, Québec, Canada (M.C.L., G.A.R., D.E.R.); and Center for Clinical Science Research, Department of Radiation Oncology, Stanford University, Stanford, California (D.A.C., A.J.G.)

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 -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- subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF-1 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.

Address correspondence to: Dr. Darren E. Richard, Centre de recherche de L'Hôtel-Dieu de Québec, 10 Rue McMahon, Québec QC G1R 2J6, Canada. E-mail: darren.richard{at}crhdq.ulaval.ca