Targeting HIF‐2α in renal cell carcinoma: Expanding upon belzutifan

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common subtype of kidney cancer driven by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the accumulation of hypoxia-inducible factor (HIF)-2α and tumorigenesis. METHODS: Targeting HIF-2α has emerged as a promising therapeutic strategy culminating in the development of a first-in-class inhibitor, belzutifan, invented by Peloton Therapeutics and marketed by Merck. This article presents the journey to belzutifan and subsequent developments. RESULTS: We discuss the structure-based design leading to the first-in-human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977/belzutifan. Detailed analyses are presented of key HIF-2α structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan's impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA-based therapeutics, are presented. Alternative HIF-2α inhibitors are examined, including NKT2152 and AB521. CONCLUSIONS: By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.