2. Academic Validation
  3. Targeting and dissociating HIF2α from the molecular chaperone Hsp70 triggers apoptosis in kidney cancer

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

  • Commun Med (Lond). 2026 Jan 12;6(1):91. doi: 10.1038/s43856-025-01356-x.
Jennifer A Heritz 1 2 3,  Sarah J Backe 1 2,  Angela Pacherille 4,  Sara J Cayaban 1 2,  Michael F Basin 1 2,  Britannia Smith 1 2,  Rebecca A Sager 1 2,  Michael Daneshvar 5,  Dawn E Post 1 2,  Mark R Woodford 1 2 3,  Dimitra Bourboulia 1 2 3,  John D Chisholm 6,  Mehdi Mollapour 7 8 9,  Gennady Bratslavsky 10 11 12
Affiliations

Affiliations

  • 1 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 2 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 3 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 4 Department of Chemistry, Syracuse University, Syracuse, NY, USA.
  • 5 Department of Urology, University of California, Irvine, CA, USA.
  • 6 Department of Chemistry, Syracuse University, Syracuse, NY, USA. [email protected].
  • 7 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 8 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 9 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 10 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 11 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 12 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
PMID: 41526504 DOI: 10.1038/s43856-025-01356-x
Abstract

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.

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