Discovery of NKT2152, a Potent and Selective HIF-2α Inhibitor with Favorable Pharmacokinetic Properties

Clear cell renal cell carcinoma (ccRCC) is driven in most cases (>80%) by inactivation of the von Hippel-Lindau (VHL) tumor suppressor, resulting in hypoxia inducible factor 2α (HIF-2α) accumulation and constitutive activation of downstream oncogenic pathways. Pharmacological inhibition of HIF-2α, exemplified by belzutifan (PT2977), has shown efficacy in ccRCC. Here, we report the discovery of NKT2152 (Imdatifan), a potent, selective, and orally available small molecule HIF-2α inhibitor identified through rational design. NKT2152 disrupts the HIF-2α/HIF-1β complex, selectively suppressing target gene expression in VHL-deficient 786-O ccRCC cells. The compound exhibits favorable pharmacokinetics in preclinical species and high brain penetration, suggesting potential utility against brain metastases. In Phase I studies, NKT2152 displays low clearance and a prolonged half-life (∼38 days), enabling sustained target inhibition. These attributes support its continued clinical development for advanced renal cell carcinoma and other solid tumors.