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Updated: Aug 14, 2026
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Eli M Wallace1, James P Rizzi2, Guangzhou Han2
1Peloton Therapeutics, Inc., Dallas, Texas. eli.wallace@pelotontx.com.
Abstract:
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.
Insights
A new drug, PT2385, effectively targets hypoxia-inducible factor 2 alpha (HIF2α), a key driver in clear cell renal cell carcinoma (ccRCC). This targeted therapy shows significant tumor regression in preclinical models with improved tolerability.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Clear cell renal cell carcinoma (ccRCC) is primarily driven by the inactivation of the von Hippel-Lindau (pVHL) tumor suppressor.
- pVHL inactivation leads to the stabilization of hypoxia-inducible factors (HIFs), promoting ccRCC initiation and progression.
Purpose of the Study:
- To investigate the efficacy of PT2385, a novel small-molecule inhibitor, as a specific antagonist of HIF2α in ccRCC.
- To evaluate the therapeutic potential of targeting HIF2α in ccRCC treatment.
Main Methods:
- PT2385 was characterized as a selective, orally active inhibitor of HIF2α dimerization with ARNT/HIF1β.
- Inhibition of HIF2α-dependent gene expression (VEGF-A, PAI-1, cyclin D1) was assessed in ccRCC cell lines and xenografts.
- Antitumor efficacy and tolerability of PT2385 were evaluated in tumor-bearing mice.
Main Results:
- PT2385 demonstrated potent inhibition of HIF2α-dependent genes in ccRCC models.
- Treatment with PT2385 resulted in significant tumor regressions in preclinical studies.
- PT2385 showed no adverse cardiovascular effects, distinguishing it from VEGF-targeting agents.
Conclusions:
- HIF2α is a critical oncogenic driver in ccRCC, and its inhibition represents a viable therapeutic strategy.
- PT2385 is a novel therapeutic agent for ccRCC with potent preclinical efficacy and improved tolerability compared to current VEGF pathway inhibitors.
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