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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> <p></p>

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Targeting and dissociating HIF2α from the molecular chaperone Hsp70 triggers apoptosis in kidney cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Jennifer A. Heritz,
  • Sarah J. Backe,
  • Angela Pacherille,
  • Sara J. Cayaban,
  • Michael F. Basin,
  • Britannia Smith,
  • Rebecca A. Sager,
  • Michael Daneshvar,
  • Dawn E. Post,
  • Mark R. Woodford,
  • Dimitra Bourboulia,
  • John D. Chisholm,
  • Mehdi Mollapour,
  • Gennady Bratslavsky

摘要

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.