Identification of a small molecule inhibitor of hypoxia-inducible factor (HIF) pathway.

Abstract

2047

Hypoxia response in solid tumors is largely mediated by the hypoxia inducible factor-1 (HIF-1), a heterodimer composed of oxygen-regulated HIF-1α and constitutively expressed HIF-1β subunits. HIF-1 controls the expression of more than 40 target genes, which plays crucial roles in tumor growth by activating anaerobic metabolism, increasing resistance to apoptosis and the production of angiogenic factors. In human cancers, HIF-1α is overexpressed as a result of intratumoral hypoxia and genetic alterations affecting key oncogenes and tumor suppressor genes. Inhibition of HIF-1 activity is therefore considered as a novel molecular target for tumor therapy. In our laboratory, we have screened a 10,000-membered natural product-like combinatorial library and identified a small molecule which specifically inhibits HIF/HRE pathways. It has low cytotoxicity under normoxia and hypoxia, while specifically decreasing HIF-1α levels in glioma cell lines induced by hypoxia in a dose- and time-dependent manner with IC₅₀ 7 μM. This inhibitor could serve as a lead compound for the development of clinically useful agents for cancer therapy targeting tumor hypoxia.