Discovery of NKT2152, a Potent and Selective HIF-2α Inhibitor with Favorable Pharmacokinetic Properties
Jiping Fu1, Yigang He1, Jing Lu1
1NiKang Therapeutics Inc., 200 Powder Mill Rd., Bldg E500, Wilmington, Delaware 19803, United States.
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.
Insights
A new drug, NKT2152 (Imdatifan), effectively inhibits hypoxia-inducible factor 2-alpha (HIF-2α) in clear cell renal cell carcinoma (ccRCC). This orally available compound shows promise for treating advanced ccRCC and other solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Clear cell renal cell carcinoma (ccRCC) is predominantly driven by von Hippel-Lindau (VHL) tumor suppressor inactivation (>80% of cases).
- VHL inactivation leads to hypoxia-inducible factor 2-alpha (HIF-2α) accumulation, activating oncogenic pathways.
- Existing HIF-2α inhibitors like belzutifan show efficacy, highlighting the therapeutic potential of targeting this pathway in ccRCC.
Purpose of the Study:
- To report the discovery and preclinical characterization of NKT2152 (Imdatifan), a novel small molecule inhibitor of HIF-2α.
- To evaluate the compound's potency, selectivity, pharmacokinetic profile, and potential efficacy in VHL-deficient ccRCC models.
- To assess the clinical potential of NKT2152 for advanced renal cell carcinoma and other solid tumors, including brain metastases.
Main Methods:
- Rational drug design was employed to identify NKT2152.
- In vitro studies assessed NKT2152's ability to disrupt the HIF-2α/HIF-1β complex and suppress target gene expression in VHL-deficient 786-O ccRCC cells.
- Preclinical pharmacokinetic studies in relevant species were conducted.
- Phase I clinical studies evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of NKT2152.
Main Results:
- NKT2152 (Imdatifan) was identified as a potent, selective, and orally available HIF-2α inhibitor.
- The compound effectively suppressed HIF-2α target gene expression in VHL-deficient ccRCC cells.
- NKT2152 demonstrated favorable pharmacokinetics in preclinical models and high brain penetration.
- Phase I studies revealed low clearance and a prolonged half-life (approximately 38 days) in humans, allowing for sustained target inhibition.
Conclusions:
- NKT2152 (Imdatifan) represents a promising new therapeutic agent for ccRCC and potentially other solid tumors.
- Its potent inhibition of HIF-2α, favorable PK profile, and sustained target engagement support its continued clinical development.
- The compound's ability to penetrate the brain suggests potential efficacy against ccRCC brain metastases.
Related Concept Videos
01:26Drug Discovery: Overview
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase