Work

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

Year: 2026

Type: article

Abstract: 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. 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. 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. 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. Cancer occurs when cells grow out of control. In the most common type of kidney cancer, this is caused by abnormal activity of a specific part of cellular machinery. In this study, we used computer simulations to find drugs that can stop this growth-causing activity. By testing drugs identified from these simulations, we found one drug that kills kidney cancer cells, but not normal cells. We show that this drug works differently than another drug used to kill kidney cancer. These results show that in the future, this drug could be used to treat kidney cancer, particularly in patients where other available drugs have not worked. Heritz et al. use an orthogonal approach to identify a selective inhibitor for HIF2α that disrupts its interaction with the molecular chaperone Hsp70. This inhibitor utilizes an alternative mechanism of action to previous HIF2α antagonists, providing a promising approach in addressing kidney cancer drug resistance.

Source: Communications Medicine

DOI: 10.1038/s43856-025-01356-x