Abstract 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.
Rodríguez et al. (Sun,) studied this question.
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