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Targeting and dissociating HIF2α from the molecular chaperone Hsp70 triggers apoptosis in kidney cancer
Jennifer A Heritz1,2,3, Sarah J Backe1,2, Angela Pacherille4
1Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
Background:
The transcription factor Hypoxia-Inducible Factor 2α (HIF2α) plays a crucial role in cancer cell adaptation to hypoxic conditions, particularly in clear cell renal cell carcinoma, promoting tumor growth and angiogenesis. Targeting HIF2α through pharmacologic inhibition offers a promising therapeutic strategy for HIF2α-driven cancers.
Methods:
An in silico docking study using 10,000 drug-like compounds was performed using the previously solved X-ray crystal structure of HIF2α. Select compounds predicted to bind to the Per-Arnt-Sim-A (PAS-A) and PAS-B domains of HIF2α were further evaluated for biological activity in clear cell renal cell carcinoma and normal kidney cell lines. Biochemical and cell-based assays were performed to define the mechanism of action for a lead compound.
Results:
Here, we identify Compound-c2 as a selective HIF2α inhibitor that binds to the PAS-B domain of HIF2α. Notably, Compound-c2 disrupts the interaction between HIF2α and the molecular chaperone Hsp70, leading to proteasomal degradation of HIF2α and the induction of apoptosis in ccRCC.
Conclusions:
The distinctive inhibitory mechanism of the HIF2α inhibitor identified here, Compound-c2, sets it apart from previous HIF2α antagonists. This positions Compound-c2 as a promising alternative with potential applications in addressing drug resistance, providing a unique approach to inhibit HIF2α-related processes.
Insights
A new compound, Compound-c2, selectively inhibits Hypoxia-Inducible Factor 2α (HIF2α) by targeting its PAS-B domain. This novel HIF2α inhibitor promotes cancer cell apoptosis and offers a promising strategy for treating clear cell renal cell carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Hypoxia-Inducible Factor 2α (HIF2α) is critical for cancer cell survival under low-oxygen conditions, driving tumor growth and angiogenesis, especially in clear cell renal cell carcinoma (ccRCC).
- Targeting HIF2α pharmacologically presents a viable therapeutic avenue for HIF2α-dependent malignancies.
Purpose of the Study:
- To identify novel small molecules that selectively inhibit HIF2α.
- To elucidate the mechanism of action of a newly identified HIF2α inhibitor.
Main Methods:
- An in silico docking approach screened 10,000 compounds against the HIF2α structure.
- Selected compounds were tested for biological activity in ccRCC and normal kidney cell lines.
- Biochemical and cell-based assays were employed to determine the mechanism of action.
Main Results:
- Compound-c2 was identified as a selective HIF2α inhibitor binding to the PAS-B domain.
- Compound-c2 disrupts the HIF2α-Hsp70 interaction, inducing HIF2α proteasomal degradation.
- This leads to apoptosis induction in ccRCC cells.
Conclusions:
- Compound-c2 exhibits a unique inhibitory mechanism distinct from other HIF2α antagonists.
- This novel compound shows potential for overcoming drug resistance in HIF2α-driven cancers.
- Compound-c2 represents a promising therapeutic candidate for targeting HIF2α-related pathways.
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