On 27 September 2022, an online article entitled ‘Structural Basis for the Allosteric Inhibition of Hypoxia-Inducible Factor 2 by Belzutifan’ was published in Molecular Pharmacology. Xintong Ren, a graduated master's student of Wulab, was the first author, and Prof. Dalei Wu and Dr. Jingjing Zhuang were the co-corresponding authors.

Hypoxia-inducible factors (HIFs) belong to the basic helix-loop-helix PER ARNT SIM (bHLH-PAS) family, which are transcription factors that respond to changes in oxygen concentration. HIF-2α has been shown to be a key oncogenic driver of clear cell renal cell carcinoma (ccRCC) and is considered an effective target for the treatment of renal cell carcinoma. Belzutifan was approved by FDA as the first marketed HIF-2α inhibitor for the treatment of cancers such as VHL-associated renal cell carcinoma in 2021, but the molecular mechanism was still unclear.

In this article, the structure of HIF-2α-ARNT-belzutifan complex was analysed, and the inhibitory mechanism of Belzutifan was explored in combination with biochemical and cellular experiments. It was found that Belzutifan binds to the PAS-B pocket of HIF-2α and forces the side chain of Met252 of HIF-2α to be displaced, destabilising the dimeric interface of HIF-2α and ARNT through a metastable effect. In addition, it was demonstrated that Belzutifan effectively reduces the transcription of HIF-2α downstream genes in 786-O cells in a dose-dependent manner in the results of real-time fluorescence quantitative PCR.

This work elucidated the mechanism of action of Belzutifan in inhibiting HIF-2α transcriptional activity through metamorphosis, which provided clues for the subsequent study of oncology drug resistance and was of great guiding significance for the design and development of new HIF-2α inhibitors.

The research was supported by Core Facilities for Life and Environmental Sciences of Shandong University, National Facility for Protein Science in Shanghai and Shanghai Synchrotron Radiation Facility.

Full text link: https://molpharm.aspetjournals.org/content/early/2022/09/27/molpharm.122.000525

Figure source: Xintong Ren

Editor: Fengyao Li