Inhibiting the hypoxia response for cancer therapy: the new kid on the block

Abstract

The hypoxia-inducible transcription factor (HIF)-1alpha inhibitor KC7F2 described in this issue of Clinical Cancer Research is the newest addition to an emerging class of antitumor agents targeting the hypoxia response. Here, we discuss the proposed mechanism of action of KC7F2 and its potential strengths and limitations in comparison with other promising HIF-1alpha inhibitors.

Figure 1. Pathways of HIF-1α synthesis, degradation and regulation of HIF-1 activity

The HIF-1 transcription factor is heterodimer of HIF-α and HIF-1β. Under normoxic conditions HIF-α undergoes rapid pVHL-dependent proline hydroxylation followed by ubiquitination and proteasomal degradation. When HIF-α levels increase under hypoxia it enters the nucleus to combine with HIF-1β, binding to a conserved DNA sequence, the hypoxia responsive element (HRE), to transactivate a variety of hypoxia-responsive genes. Co-activators such as p300/CREB binding protein (CBP) regulate HIF-1 activity. Reported inhibitors of HIF-1 and their putative mechanism of inhibition, where known, are shown in the boxes.