PT2977

Belzutifan is an inhibitor of hypoxia-inducible factor 2α (HIF-2α) used in the treatment of von Hippel-Lindau (VHL) disease-associated cancers. The HIF-2α protein was first identified in the 1990s by researchers at UT Southwestern Medical Center as a key player in the growth of certain cancers. Initially considered to be undruggable, a binding pocket was eventually discovered in the HIF-2α molecule which allowed for compounds to bind and inhibit these proteins. This discovery led to the initial development of belzutifan (at the time called PT2977), which was further developed by a spin-off company named Peloton Pharmaceuticals (which itself was eventually acquired by Merck in 2019). Belzutifan inhibits the complexation of HIF-2α with another transcription factor, HIF-1β, a necessary step in its activation - by preventing the formation of this complex, belzutifan can slow or stop the growth of VHL-associated tumors. Belzutifan received FDA approval for the treatment of select VHL-associated cancers on August 13, 2021. It was later approved for the treatment of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL) in patients aged 12 years and older.