Small-molecule allosteric inhibitors of GPX4

Liu, Hengrui; Forouhar, Farhad; Lin, Annie J.; Wang, Qian; Polychronidou, Vasiliki; Soni, Rajesh Kumar; Xia, Xin; Stockwell, Brent R.

doi:10.1016/j.chembiol.2022.11.003

Small-molecule allosteric inhibitors of GPX4

Journal Article · Tue Nov 22 23:00:00 EST 2022 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2022.11.003· OSTI ID:2423614

Liu, Hengrui ^[1]; Forouhar, Farhad ^[1]; Lin, Annie J. ^[1]; Wang, Qian ^[1]; Polychronidou, Vasiliki ^[1]; Soni, Rajesh Kumar ^[1]; Xia, Xin ^[1]; ^[1]

Columbia Univ., New York, NY (United States)

Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423614

Journal Information:: Cell Chemical Biology, Journal Name: Cell Chemical Biology Journal Issue: 12 Vol. 29; ISSN 2451-9456

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
GPX4
allosteric
cancer
cysteine
drug discovery
enzyme
glutathione
inhibitor
peroxidase
small molecule

Small-molecule allosteric inhibitors of GPX4

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