A Comprehensive Description of Hypoxia-inducible Factor 2α Inhibitors as Anticancer Agents: A Mini-review

Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1a, HIF-2a, and HIF-3a, of which HIF-2a has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2a plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2a has become one of the important strategies for treating cancers. HIF-2a inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2a inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.