Allosteric inhibition of HIF-2α as a novel therapy for clear cell renal cell carcinoma

• Published in: Drug discovery today 2019-12, Vol.24 (12), p.2332-2340
• Main Authors: Yu, Yancheng, Yu, Quanwei, Zhang, Xiaojin
• Format: Article
• Language: English
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2019.09.008

[Display omitted] •Summary of the downstream genes of HIF-2α involved in clear cell renal cell carcinoma.•The inhibition mechanism of HIF-2α allosteric inhibitors is described in detailed.•Two key residues affecting the activity of HIF-2α inhibitors were analyzed.•The development of two categories of HIF-2α allosteric inhibitors were reviewed. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2α (HIF-2α) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2α inhibitors to the promising potency of the HIF-2α inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2α has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2α in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2α allosteric inhibitors.