Development of small molecule inhibitors of hypoxia-inducible factors for cancer therapy

The hypoxia-inducible factors (HIFs)-HIF-1 and HIF-2-play critical roles in cancer progression by controlling the transcription of thousands of genes across the full range of human cell types. Inhibition of their activity blocks cancer growth, vascularization, and metastasis in mouse models. Small-molecule HIF inhibitors, with varying degrees of specificity and mechanism of action have been reported to have antitumor activity in mouse models. An HIF-2 inhibitor, belzutifan, has recently been approved for the treatment of renal cell carcinoma. Dual HIF-1/2 inhibitors are being developed and are likely to have utility as cancer therapeutics, particularly in combination with immune checkpoint blockade. SIGNIFICANCE STATEMENT: Hypoxia-inducible factor inhibitors represent a powerful new therapeutic approach that has the potential to improve patient survival in many types of cancer when administered in combination with existing therapies.