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Clear cell Renal Cell Carcinoma (ccRCC) is characterized in most cases (>80%) by the inactivation of von Hippel-Lindau (VHL) tumor suppressor. VHL loss leads to HIF2α accumulation and constitutive activation of its downstream genes important in carcinogenesis. Preclinical and clinical evidence demonstrate that HIF2α inhibition by the first-in-class belzutifan (MK-6482) offers an effective treatment for ccRCC. Here we discovered a novel, potent, selective, and orally available small molecule HIF2α inhibitor (NKT2152) through rational drug design. Cellular thermal shift assay demonstrated NKT2152 engaged HIF2α and stabilized it against heat-induced denaturation in ccRCC 786-O cells. NKT2152 disrupted HIF2α/HIF1β complex in a dose-dependent manner, resulting in increased cytosol localization and reduced nucleus localization of HIF2α in 786-O cells. In vitro, NKT2152 specifically suppressed the expression of HIF2α target genes including vascular endothelial growth factor A, cyclin D1, and glucose transporter 1 in 786-O cells. Pharmacodynamic analysis of NKT2152 in the 786-O xenograft tumor model confirmed that NKT2152 potently inhibited HIF2α as demonstrated by the repression of HIF2α-regulated genes at both mRNA and protein levels. Moreover, NKT2152 treatment, administrated twice daily by oral gavage, led to a dose-dependent tumor growth inhibition or tumor regression in both ccRCC cell line-derived (A498 and 786-O) and patient-derived xenograft tumor models. More pronounced tumor growth inhibition was observed when NKT2152 was combined with a VEGFR inhibitor or a CDK4/6 inhibitor in the 786-O xenograft tumor model. In addition to directly promoting tumor progression by regulating gene expression in tumor cells, HIF2α has also been proposed to play an integral role in shaping the tumor microenvironment under hypoxia. Given hypoxia is a hallmark of most solid tumors and is associated with poor survival in a wide range of cancer types, we tested the hypothesis that HIF2α inhibition by NKT2152 may exert broader anti-tumor activity in other solid tumors that lack a VHL gene deficiency. Indeed, we demonstrated here that NKT2152 caused significant tumor growth inhibition in multiple solid tumor xenograft models, including but not limited to hepatocellular carcinoma. NKT2152 had excellent oral bioavailability and achieved high exposures in mouse, rat and dog. These data not only support clinical development of NKT2152 in ccRCC, but also provide exciting opportunities for expanding to other solid tumor indications with tremendous unmet medical needs. Clinical evaluation of NKT2152 for the treatment of ccRCC is ongoing. Citation Format: Jing Lu, Hairong Wei, Wenfeng Sun, Jianlin Geng, Ke Liu, Jessica Liu, Zhihong Liu, Jiping Fu, Yigang He, Keshi Wang, Yan Lou, Zhenhai Gao. NKT2152: A highly potent HIF2α inhibitor and its therapeutic potential in solid tumors beyond ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6330. |
