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

• 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. [ABSTRACT FROM AUTHOR]