2. Academic Validation
  3. Small-molecule allosteric inhibitors of GPX4

Small-molecule allosteric inhibitors of GPX4

  • Cell Chem Biol. 2022 Dec 15;29(12):1680-1693.e9. doi: 10.1016/j.chembiol.2022.11.003.
Hengrui Liu 1,  Farhad Forouhar 2,  Annie J Lin 3,  Qian Wang 3,  Vasiliki Polychronidou 3,  Rajesh Kumar Soni 4,  Xin Xia 3,  Brent R Stockwell 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • 2 Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
  • 3 Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • 4 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
  • 5 Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
PMID: 36423641 DOI: 10.1016/j.chembiol.2022.11.003
Abstract

Encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.

Keywords

GPX4; allosteric; cancer; cysteine; drug discovery; enzyme; glutathione; inhibitor; peroxidase; small molecule.

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