ArticleACS medicinal chemistry letters2026
Discovery of NKT2152, a Potent and Selective HIF-2α Inhibitor with Favorable Pharmacokinetic Properties.
Article in ACS medicinal chemistry letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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