HC-7366 + belzutifan

**HC-7366 + belzutifan** is an investigational combination drug therapy being studied for the treatment of advanced or metastatic renal cell carcinoma (RCC) with clear cell histology. **HC-7366** is a novel, orally administered, selective and potent small molecule activator of the general control nonderepressible 2 (GCN2) kinase, a central regulator of the integrated stress response (ISR). Activation of GCN2 by HC-7366 suppresses general protein synthesis, induces cell cycle arrest, inhibits metabolism (glycolysis, oxidative phosphorylation, TCA cycle), and decreases hypoxia-inducible factor (HIF) expression in both tumor cells and immunosuppressive myeloid cells, resulting in antitumor and immunomodulatory effects. **Belzutifan** is a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α), blocking HIF-2α-mediated transcriptional activity that drives tumor growth, especially in settings of VHL deficiency. The rationale for the combination leverages complementary targeting of the HIF pathway and cellular metabolism/stress pathways, and preclinical models have shown enhanced antitumor activity compared to either agent alone, especially in clear cell RCC. The combination is currently being evaluated in a multicenter, open-label phase 1b clinical trial (NCT06234605) for advanced/metastatic RCC and is developed by HiberCell in collaboration with Merck Sharp & Dohme LLC (subsidiary of Merck & Co.).

Other names

HC-7366 + Welireg