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2000
Volume 25, Issue 1
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

Ferroptosis is a novel type of programmed cell death that relies on the build-up of intracellular iron and leads to an increase in toxic lipid peroxides. Glutathione Peroxidase 4 (GPX4) is a crucial regulator of ferroptosis that uses glutathione as a cofactor to detoxify cellular lipid peroxidation. Targeting GPX4 in cancer could be a promising strategy to induce ferroptosis and kill drug-resistant cancers effectively. Currently, research on GPX4 inhibitors is of increasing interest in the field of anti-tumor agents. Many reviews have summarized the regulation and ferroptosis induction of GPX4 in human cancer and disease. However, insufficient attention has been paid to GPX4 inhibitors. This article outlines the molecular structures and development prospects of GPX4 inhibitors as novel anticancer agents.

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2024-06-14
2024-12-26
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References

  1. DixonS.J. LembergK.M. LamprechtM.R. SkoutaR. ZaitsevE.M. GleasonC.E. PatelD.N. BauerA.J. CantleyA.M. YangW.S. MorrisonB.III StockwellB.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death.Cell201214951060107210.1016/j.cell.2012.03.04222632970
    [Google Scholar]
  2. StockwellB.R. Ferroptosis: Death by lipid peroxidation.Free Radic. Biol. Med.2018120S710.1016/j.freeradbiomed.2018.04.034
    [Google Scholar]
  3. ZhaoS. MaL. ChuZ. XuH. WuW. LiuF. Regulation of microglial activation in stroke.Acta Pharmacol. Sin.201738444545810.1038/aps.2016.16228260801
    [Google Scholar]
  4. CaoJ.Y. DixonS.J. Mechanisms of ferroptosis.Cell. Mol. Life Sci.20167311-122195220910.1007/s00018‑016‑2194‑127048822
    [Google Scholar]
  5. LiJ. CaoF. YinH. HuangZ. LinZ. MaoN. SunB. WangG. Ferroptosis: Past, present and future.Cell Death Dis.20201128810.1038/s41419‑020‑2298‑232015325
    [Google Scholar]
  6. StockwellB.R. JiangX. The chemistry and biology of ferroptosis.Cell Chem. Biol.202027436537510.1016/j.chembiol.2020.03.01332294465
    [Google Scholar]
  7. HadianK. StockwellB.R. SnapShot.Ferroptosis. Cell2020181511881188.e110.1016/j.cell.2020.04.03932470402
    [Google Scholar]
  8. ChenX. KangR. KroemerG. TangD. Broadening horizons: The role of ferroptosis in cancer.Nat. Rev. Clin. Oncol.202118528029610.1038/s41571‑020‑00462‑033514910
    [Google Scholar]
  9. TangD. KroemerG. Ferroptosis.Curr. Biol.20203021R1292R129710.1016/j.cub.2020.09.06833142092
    [Google Scholar]
  10. JiangX. StockwellB.R. ConradM. Ferroptosis: Mechanisms, biology and role in disease.Nat. Rev. Mol. Cell Biol.202122426628210.1038/s41580‑020‑00324‑833495651
    [Google Scholar]
  11. StockwellB.R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications.Cell2022185142401242110.1016/j.cell.2022.06.00335803244
    [Google Scholar]
  12. HadianK. StockwellB.R. The therapeutic potential of targeting regulated non-apoptotic cell death.Nat. Rev. Drug Discov.202322972374210.1038/s41573‑023‑00749‑837550363
    [Google Scholar]
  13. XuL. LiuY. ChenX. ZhongH. WangY. Ferroptosis in life: To be or not to be.Biomed. Pharmacother.202315911424110.1016/j.biopha.2023.11424136634587
    [Google Scholar]
  14. CaoY.Y. WangZ. WangZ.H. JiangX.G. LuW.H. Inhibition of miR-155 alleviates sepsis-induced inflammation and intestinal barrier dysfunction by inactivating NF-κB signaling.Int. Immunopharmacol.20219010721810.1016/j.intimp.2020.10721833296782
    [Google Scholar]
  15. OuM. JiangY. JiY. ZhouQ. DuZ. ZhuH. ZhouZ. Role and mechanism of ferroptosis in neurological diseases.Mol. Metab.20226110150210.1016/j.molmet.2022.10150235447365
    [Google Scholar]
  16. WangX. ZhouD. ZhouW. LiuJ. XueQ. HuangY. ChengC. WangY. ChangJ. WangP. MiaoC. Clematichinenoside AR inhibits the pathology of rheumatoid arthritis by blocking the circPTN/miR-145-5p/FZD4 signal axis.Int. Immunopharmacol.2022113PtA10937610.1016/j.intimp.2022.10937636279670
    [Google Scholar]
  17. WuM. ChenZ. JiangM. BaoB. LiD. YinX. WangX. LiuD. ZhuL.Q. Friend or foe: Role of pathological tau in neuronal death.Mol. Psychiatry20232862215222710.1038/s41380‑023‑02024‑z36918705
    [Google Scholar]
  18. LiY. XuH. WangH. YangK. LuanJ. WangS. TREM2: Potential therapeutic targeting of microglia for Alzheimer’s disease.Biomed. Pharmacother.202316511521810.1016/j.biopha.2023.11521837517293
    [Google Scholar]
  19. BelavgeniA. MeyerC. StumpfJ. HugoC. LinkermannA. Ferroptosis and necroptosis in the kidney.Cell Chem. Biol.202027444846210.1016/j.chembiol.2020.03.01632302582
    [Google Scholar]
  20. AllisonS.J. DPEP1 and CHMP1A in kidney ferroptosis.Nat. Rev. Nephrol.2021171170770710.1038/s41581‑021‑00496‑234561671
    [Google Scholar]
  21. WangY. WuH. HanZ. ShengH. WuY. WangY. GuoX. ZhuY. LiX. WangY. Guhong injection promotes post-stroke functional recovery via attenuating cortical inflammation and apoptosis in subacute stage of ischemic stroke.Phytomedicine20229915403410.1016/j.phymed.2022.15403435276592
    [Google Scholar]
  22. WangL. WangP. WangD. TaoM. XuW. OlatunjiO.J. Anti-Inflammatory activities of Kukoamine A from the root bark of lycium chinense miller.Nat. Prod. Commun.20201532091208810.1177/1934578X20912088
    [Google Scholar]
  23. HeC. JiangY. GuoY. WuZ. Amplified ferroptosis and apoptosis facilitated by differentiation therapy efficiently suppress the progression of Osteosarcoma.Small20231944230257510.1002/smll.20230257537394717
    [Google Scholar]
  24. LiuJ.Q. ZhaoX.T. QinF.Y. ZhouJ.W. DingF. ZhouG. ZhangX.S. ZhangZ.H. LiZ.B. Isoliquiritigenin mitigates oxidative damage after subarachnoid hemorrhage in vivo and in vitro by regulating Nrf2-dependent Signaling Pathway via Targeting of SIRT1.Phytomedicine202210515426210.1016/j.phymed.2022.15426235896045
    [Google Scholar]
  25. LeiG. ZhuangL. GanB. Targeting ferroptosis as a vulnerability in cancer.Nat. Rev. Cancer202222738139610.1038/s41568‑022‑00459‑035338310
    [Google Scholar]
  26. YanH. ZouT. TuoQ. XuS. LiH. BelaidiA.A. LeiP. Ferroptosis: Mechanisms and links with diseases.Signal Transduct. Target. Ther.2021614910.1038/s41392‑020‑00428‑933536413
    [Google Scholar]
  27. TaiP. ChenX. JiaG. ChenG. GongL. ChengY. LiZ. WangH. ChenA. ZhangG. ZhuY. XiaoM. WangZ. LiuY. ShanD. HeD. LiM. ZhanT. KhanA. LiX. ZengX. LiC. OuyangD. AiK. ChenX. LiuD. LiuZ. WeiD. CaoK. WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.J. Transl. Med.202321182310.1186/s12967‑023‑04715‑137978379
    [Google Scholar]
  28. WangX. WangX. YaoH. ShenC. GengK. XieH. A comprehensive review on Schisandrin and its pharmacological features.Naunyn Schmiedebergs Arch. Pharmacol.2024397278379410.1007/s00210‑023‑02687‑z37658213
    [Google Scholar]
  29. WangX. LeiW. LiuC. YangJ. ZhuY.H. BOLA3 is a prognostic-related biomarker and correlated with immune infiltrates in lung adenocarcinoma.Int. Immunopharmacol.202210710865210.1016/j.intimp.2022.10865235286914
    [Google Scholar]
  30. MaoC. GanB. Navigating ferroptosis via an NADPH sensor.Nat. Cell Biol.20222481186118710.1038/s41556‑022‑00963‑335941366
    [Google Scholar]
  31. ZhengJ. ConradM. The metabolic underpinnings of ferroptosis.Cell Metab.202032692093710.1016/j.cmet.2020.10.01133217331
    [Google Scholar]
  32. DollS. FreitasF.P. ShahR. AldrovandiM. da SilvaM.C. IngoldI. Goya GrocinA. Xavier da SilvaT.N. PanziliusE. ScheelC.H. MourãoA. BudayK. SatoM. WanningerJ. VignaneT. MohanaV. RehbergM. FlatleyA. SchepersA. KurzA. WhiteD. SauerM. SattlerM. TateE.W. SchmitzW. SchulzeA. O’DonnellV. PronethB. PopowiczG.M. PrattD.A. AngeliJ.P.F. ConradM. FSP1 is a glutathione-independent ferroptosis suppressor.Nature2019575778469369810.1038/s41586‑019‑1707‑031634899
    [Google Scholar]
  33. MurphyM.P. Metabolic control of ferroptosis in cancer.Nat. Cell Biol.201820101104110510.1038/s41556‑018‑0209‑x30224762
    [Google Scholar]
  34. LeeH. ZandkarimiF. ZhangY. MeenaJ.K. KimJ. ZhuangL. TyagiS. MaL. WestbrookT.F. SteinbergG.R. NakadaD. StockwellB.R. GanB. Energy-stress-mediated AMPK activation inhibits ferroptosis.Nat. Cell Biol.202022222523410.1038/s41556‑020‑0461‑832029897
    [Google Scholar]
  35. ZhaL. PanL. GuoJ. FrenchN. VillanuevaE.V. TefsenB. Effectiveness and safety of high dose tigecycline for the treatment of severe infections: A systematic review and meta-analysis.Adv. Ther.20203731049106410.1007/s12325‑020‑01235‑y32006240
    [Google Scholar]
  36. SeibtT.M. PronethB. ConradM. Role of GPX4 in ferroptosis and its pharmacological implication.Free Radic. Biol. Med.201913314415210.1016/j.freeradbiomed.2018.09.01430219704
    [Google Scholar]
  37. ForcinaG.C. DixonS.J. GPX4 at the crossroads of lipid homeostasis and ferroptosis.Proteomics20191918180031110.1002/pmic.20180031130888116
    [Google Scholar]
  38. MaoC. LiuX. ZhangY. LeiG. YanY. LeeH. KoppulaP. WuS. ZhuangL. FangB. PoyurovskyM.V. OlszewskiK. GanB. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.Nature2021593786058659010.1038/s41586‑021‑03539‑733981038
    [Google Scholar]
  39. ChenW.G. ZhangS.S. PanS. WangZ.F. XuJ.Y. ShengX.H. YinQ. WuY.J. α-Mangostin treats early-stage adjuvant-induced arthritis of rat by regulating the CAP-SIRT I pathway in macrophages.Drug Des. Devel. Ther.20221650952010.2147/DDDT.S34883635250263
    [Google Scholar]
  40. SunS. WangY. DuY. SunQ. HeL. ZhuE. LiJ. Oxidative stress-mediated hepatotoxicity in rats induced by ethanol extracts of different parts of Chloranthus serratu s.Pharm. Biol.20205811286129810.1080/13880209.2020.185955233355514
    [Google Scholar]
  41. UrsiniF. Bosello TravainV. CozzaG. MiottoG. RoveriA. ToppoS. MaiorinoM. A white paper on Phospholipid Hydroperoxide Glutathione Peroxidase (GPx4) forty years later.Free Radic. Biol. Med.202218811713310.1016/j.freeradbiomed.2022.06.22735718302
    [Google Scholar]
  42. WangG. ZhangH. SunJ. ZhangY. HeF. ZouJ. Cyclosporin A impairs neurogenesis and cognitive abilities in brain development via the IFN-γ-Shh-BDNF pathway.Int. Immunopharmacol.20219610774410.1016/j.intimp.2021.107744
    [Google Scholar]
  43. JiangY.X. LiW. WangJ. WangG.G. Cardiac dysfunction is attenuated by ginkgolide B via reducing oxidative stress and fibrosis in diabetic rats.Iran. J. Basic Med. Sci.20202381078108432952955
    [Google Scholar]
  44. LabrecqueC.L. FuglestadB. Electrostatic drivers of GPx4 interactions with membrane, lipids, and DNA.Biochemistry202160372761277210.1021/acs.biochem.1c0049234492183
    [Google Scholar]
  45. HangauerM.J. ViswanathanV.S. RyanM.J. BoleD. EatonJ.K. MatovA. GaleasJ. DhruvH.D. BerensM.E. SchreiberS.L. McCormickF. McManusM.T. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.Nature2017551767924725010.1038/nature2429729088702
    [Google Scholar]
  46. LiY. DaiM. WangL. WangG. Polysaccharides and glycosides from Aralia echinocaulis protect rats from arthritis by modulating the gut microbiota composition.J. Ethnopharmacol.202126911374910.1016/j.jep.2020.11374933359861
    [Google Scholar]
  47. ChenJ. CaoD. JiangS. LiuX. PanW. CuiH. YangW. LiuZ. JinJ. ZhaoZ. Triterpenoid saponins from Ilex pubescens promote blood circulation in blood stasis syndrome by regulating sphingolipid metabolism and the PI3K/AKT/eNOS signaling pathway.Phytomedicine202210415424210.1016/j.phymed.2022.15424235728385
    [Google Scholar]
  48. StockwellB. Ferroptosis: Mechanisms and therapeutic applications.Free Radic. Biol. Med.2017112710.1016/j.freeradbiomed.2017.10.355
    [Google Scholar]
  49. ScheererP. BorchertA. KraussN. WessnerH. GerthC. HöhneW. KuhnH. Structural basis for catalytic activity and enzyme polymerization of phospholipid hydroperoxide glutathione peroxidase-4 (GPx4).Biochemistry200746319041904910.1021/bi700840d17630701
    [Google Scholar]
  50. MaiorinoM. ConradM. UrsiniF. GPx4, lipid peroxidation, and cell death: Discoveries, rediscoveries, and open issues.Antioxid. Redox Signal.2018291617410.1089/ars.2017.711528462584
    [Google Scholar]
  51. BorchertA. KalmsJ. RothS.R. RademacherM. SchmidtA. HolzhutterH.G. KuhnH. ScheererP. Crystal structure and functional characterization of selenocysteine-containing glutathione peroxidase 4 suggests an alternative mechanism of peroxide reduction.Biochim. Biophys. Acta Mol. Cell Biol. Lipids2018186391095110710.1016/j.bbalip.2018.06.00629883798
    [Google Scholar]
  52. IngoldI. BerndtC. SchmittS. DollS. PoschmannG. BudayK. RoveriA. PengX. Porto FreitasF. SeibtT. MehrL. AichlerM. WalchA. LampD. JastrochM. MiyamotoS. WurstW. UrsiniF. ArnérE.S.J. Fradejas-VillarN. SchweizerU. ZischkaH. Friedmann AngeliJ.P. ConradM. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis.Cell20181723409422.e2110.1016/j.cell.2017.11.04829290465
    [Google Scholar]
  53. Friedmann AngeliJ.P. ConradM. Selenium and GPX4, a vital symbiosis.Free Radic. Biol. Med.201812715315910.1016/j.freeradbiomed.2018.03.00129522794
    [Google Scholar]
  54. MousaR. Notis DardashtiR. MetanisN. Selenium and selenocysteine in protein chemistry.Angew. Chem. Int. Ed.20175650158181582710.1002/anie.20170687628857389
    [Google Scholar]
  55. MoosmayerD. HilpmannA. HoffmannJ. SchnirchL. ZimmermannK. BadockV. FurstL. EatonJ.K. ViswanathanV.S. SchreiberS.L. GradlS. HilligR.C. Crystal structures of the selenoprotein glutathione peroxidase 4 in its apo form and in complex with the covalently bound inhibitor ML162.Acta Crystallogr. D Struct. Biol.202177223724810.1107/S205979832001612533559612
    [Google Scholar]
  56. LiuH. ForouharF. SeibtT. SanetoR. WigbyK. FriedmanJ. XiaX. ShchepinovM.S. RameshS.K. ConradM. StockwellB.R. Characterization of a patient-derived variant of GPX4 for precision therapy.Nat. Chem. Biol.20221819110010.1038/s41589‑021‑00915‑234931062
    [Google Scholar]
  57. UrsiniF. MaiorinoM. Lipid peroxidation and ferroptosis: The role of GSH and GPx4.Free Radic. Biol. Med.202015217518510.1016/j.freeradbiomed.2020.02.02732165281
    [Google Scholar]
  58. CozzaG. RossettoM. Bosello-TravainV. MaiorinoM. RoveriA. ToppoS. ZaccarinM. ZennaroL. UrsiniF. Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: The polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center.Free Radic. Biol. Med.201711211110.1016/j.freeradbiomed.2017.07.01028709976
    [Google Scholar]
  59. WuZ. KhodadeV.S. ChauvinJ.P.R. RodriguezD. ToscanoJ.P. PrattD.A. Hydropersulfides inhibit lipid peroxidation and protect cells from ferroptosis.J. Am. Chem. Soc.202214434158251583710.1021/jacs.2c0680435977425
    [Google Scholar]
  60. WangD. LiX. GongG. LuY. GuoZ. ChenR. HuangH. LiZ. BianJ. An updated patent review of glutaminase inhibitors (2019–2022).Expert Opin. Ther. Pat.2023331172810.1080/13543776.2023.217357336698323
    [Google Scholar]
  61. ViswanathanV.S. RyanM.J. DhruvH.D. GillS. EichhoffO.M. Seashore-LudlowB. KaffenbergerS.D. EatonJ.K. ShimadaK. AguirreA.J. ViswanathanS.R. ChattopadhyayS. TamayoP. YangW.S. ReesM.G. ChenS. BoskovicZ.V. JavaidS. HuangC. WuX. TsengY.Y. RoiderE.M. GaoD. ClearyJ.M. WolpinB.M. MesirovJ.P. HaberD.A. EngelmanJ.A. BoehmJ.S. KotzJ.D. HonC.S. ChenY. HahnW.C. LevesqueM.P. DoenchJ.G. BerensM.E. ShamjiA.F. ClemonsP.A. StockwellB.R. SchreiberS.L. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.Nature2017547766445345710.1038/nature2300728678785
    [Google Scholar]
  62. JiaM. QinD. ZhaoC. ChaiL. YuZ. WangW. TongL. LvL. WangY. RehwinkelJ. YuJ. ZhaoW. Redox homeostasis maintained by GPX4 facilitates STING activation.Nat. Immunol.202021772773510.1038/s41590‑020‑0699‑032541831
    [Google Scholar]
  63. ZhouW. YangK. ZengJ. LaiX. WangX. JiC. LiY. ZhangP. LiS. FordNet: Recommending traditional Chinese medicine formula via deep neural network integrating phenotype and molecule.Pharmacol. Res.202117310575210.1016/j.phrs.2021.10575234481072
    [Google Scholar]
  64. WeïwerM. BittkerJ.A. LewisT.A. ShimadaK. YangW.S. MacPhersonL. DandapaniS. PalmerM. StockwellB.R. SchreiberS.L. MunozB. Development of small-molecule probes that selectively kill cells induced to express mutant RAS.Bioorg. Med. Chem. Lett.20122241822182610.1016/j.bmcl.2011.09.04722297109
    [Google Scholar]
  65. KimJ.W. MinD.W. KimD. KimJ. KimM.J. LimH. LeeJ.Y. GPX4 overexpressed non-small cell lung cancer cells are sensitive to RSL3-induced ferroptosis.Sci. Rep.2023131887210.1038/s41598‑023‑35978‑937258589
    [Google Scholar]
  66. YangW.S. SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A.; Shamji, A.F.; Clish, C.B.; Brown, L.M.; Girotti, A.W.; Cornish, V.W.; Schreiber, S.L.; Stockwell, B.R. Regulation of ferroptotic cancer cell death by GPX4.Cell20141561-231733110.1016/j.cell.2013.12.01024439385
    [Google Scholar]
  67. YangW.S. KimK.J. GaschlerM.M. PatelM. ShchepinovM.S. StockwellB.R. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.Proc. Natl. Acad. Sci. USA201611334E4966E497510.1073/pnas.160324411327506793
    [Google Scholar]
  68. RandolphJ.T. O’ConnorM.J. HanF. HutchinsC.W. SiuY.A. ChoM. ZhengY. HicksonJ.A. MarkleyJ.L. ManavesV. AlgireM. BakerK.A. ChapmanA.M. GopalakrishnanS.M. PanchalS.C. Foster-DukeK. StolarikD.F. Kempf-GroteA. DammeierD. FosseyS. SunQ. SunC. ShenY. DartM.J. KatiW.M. LaiA. FirestoneA.J. KortM.E. Discovery of a potent chloroacetamide GPX4 inhibitor with bioavailability to enable target engagement in mice, a potential tool compound for inducing ferroptosis in vivo.J. Med. Chem.20236663852386510.1021/acs.jmedchem.2c0141536877935
    [Google Scholar]
  69. ChenT. LengJ. TanJ. ZhaoY. XieS. ZhaoS. YanX. ZhuL. LuoJ. KongL. YinY. Discovery of novel potent covalent glutathione peroxidase 4 inhibitors as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer.J. Med. Chem.20236614100361005910.1021/acs.jmedchem.3c0096737452764
    [Google Scholar]
  70. XuC. XiaoZ. WangJ. LaiH. ZhangT. GuanZ. XiaM. ChenM. RenL. HeY. GaoY. ZhaoC. Discovery of a potent glutathione peroxidase 4 inhibitor as a selective ferroptosis inducer.J. Med. Chem.20216418133121332610.1021/acs.jmedchem.1c0056934506134
    [Google Scholar]
  71. EatonJ.K. FurstL. CaiL.L. ViswanathanV.S. SchreiberS.L. Structure–activity relationships of GPX4 inhibitor warheads.Bioorg. Med. Chem. Lett.2020302312753810.1016/j.bmcl.2020.12753832920142
    [Google Scholar]
  72. NauserT. SteinmannD. KoppenolW.H. Why do proteins use selenocysteine instead of cysteine?Amino Acids2012421394410.1007/s00726‑010‑0602‑720461421
    [Google Scholar]
  73. MuttenthalerM. AlewoodP.F. Selenopeptide chemistry.J. Pept. Sci.200814121223123910.1002/psc.107518951416
    [Google Scholar]
  74. CordonM.B. JacobsenK.M. NielsenC.S. HjerrildP. PoulsenT.B. Forward chemical genetic screen for oxygen-dependent cytotoxins uncovers new covalent fragments that target GPX4.ChemBioChem2022231e20210025310.1002/cbic.20210025334252249
    [Google Scholar]
  75. KarajE. SindiS.H. KuganesanN. PereraL. TaylorW. TillekeratneL.M.V. Tunable cysteine-targeting electrophilic heteroaromatic warheads induce ferroptosis.J. Med. Chem.20226517117881181710.1021/acs.jmedchem.2c0090935984756
    [Google Scholar]
  76. EatonJ.K. FurstL. RubertoR.A. MoosmayerD. HilpmannA. RyanM.J. ZimmermannK. CaiL.L. NiehuesM. BadockV. KrammA. ChenS. HilligR.C. ClemonsP.A. GradlS. MontagnonC. LazarskiK.E. ChristianS. BajramiB. NeuhausR. EheimA.L. ViswanathanV.S. SchreiberS.L. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles.Nat. Chem. Biol.202016549750610.1038/s41589‑020‑0501‑532231343
    [Google Scholar]
  77. EatonJ.K. RubertoR.A. KrammA. ViswanathanV.S. SchreiberS.L. Diacylfuroxans are masked nitrile oxides that inhibit GPX4 covalently.J. Am. Chem. Soc.201914151204072041510.1021/jacs.9b1076931841309
    [Google Scholar]
  78. KathmanS.G. CravattB.F. A masked zinger to block GPX4.Nat. Chem. Biol.202016548248310.1038/s41589‑020‑0511‑332231342
    [Google Scholar]
  79. LiuS.J. ZhaoQ. PengC. MaoQ. WuF. ZhangF.H. FengQ.S. HeG. HanB. Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation.Eur. J. Med. Chem.202121711335910.1016/j.ejmech.2021.11335933725632
    [Google Scholar]
  80. LuanD. GuoW. GaoX. XuK. TangB. Visualization of the process: Selenocysteine activates GPX4 in ferroptosis based on a nano-fluorescent probe.Sci. China Chem.20226571286129010.1007/s11426‑022‑1250‑5
    [Google Scholar]
  81. LuX. SmaillJ.B. DingK. New promise and opportunities for allosteric kinase inhibitors.Angew. Chem. Int. Ed.20205933137641377610.1002/anie.20191452531889388
    [Google Scholar]
  82. WangC. WangR. WangH. ZangL. XuH. HuangC. ChenY. WangL. A link between chemical structure and biological activity in triterpenoids.Recent Patents Anticancer Drug Discov.202217214516110.2174/157489281666621051203163533982656
    [Google Scholar]
  83. LiuH. ForouharF. LinA.J. WangQ. PolychronidouV. SoniR.K. XiaX. StockwellB.R. Small-molecule allosteric inhibitors of GPX4.Cell Chem. Biol.2022291216801693.e910.1016/j.chembiol.2022.11.00336423641
    [Google Scholar]
  84. BoikeL. HenningN.J. NomuraD.K. Advances in covalent drug discovery.Nat. Rev. Drug Discov.2022211288189810.1038/s41573‑022‑00542‑z36008483
    [Google Scholar]
  85. CaoY. WuB. XuY. WangM. WuX. LiangX. LinJ. LiZ. LinH. LuoC. ChenS. Discovery of GPX4 inhibitors through FP-based high-throughput screening.Eur. J. Med. Chem.202426511604410.1016/j.ejmech.2023.11604438145603
    [Google Scholar]
  86. TangZ. LiJ. PengL. XuF. TanY. HeX. ZhuC. ZhangZ-M. ZhangZ. SunP. DingK. LiZ. Novel covalent probe selectively targeting glutathione peroxidase 4 in vivo: Potential applications in pancreatic cancer therapy.J. Med. Chem.20246731872188710.1021/acs.jmedchem.3c01608
    [Google Scholar]
  87. LiuS. ZhangH.L. LiJ. YeZ.P. DuT. LiL.C. GuoY.Q. YangD. LiZ.L. CaoJ.H. HuB.X. ChenY.H. FengG.K. LiZ.M. DengR. HuangJ.J. ZhuX.F. Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis.Redox Biol.20236210267710.1016/j.redox.2023.10267736989572
    [Google Scholar]
  88. PamarthyD. BeheraS.K. SwainS. YadavS. SureshS. JainN. BhadraM.P. Diaryl ether derivative inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells.Drug Dev. Res.202384586188710.1002/ddr.2205937070554
    [Google Scholar]
  89. LiY. RanQ. DuanQ. JinJ. WangY. YuL. WangC. ZhuZ. ChenX. WengL. LiZ. WangJ. WuQ. WangH. TianH. SongS. ShanZ. ZhaiQ. QinH. ChenS. FangL. YinH. ZhouH. JiangX. WangP. 7-Dehydrocholesterol dictates ferroptosis sensitivity.Nature2024626799841141810.1038/s41586‑023‑06983‑938297130
    [Google Scholar]
  90. WangW. MaF. CheungY.T. ZengG. ZhouY. ChenZ. LiangL. LuoT. TongR. Marine alkaloid lepadins E and H induce ferroptosis for cancer chemotherapy.J. Med. Chem.20236616112011121510.1021/acs.jmedchem.3c0065937578947
    [Google Scholar]
  91. HuaZ. HuiL.I. HaihuaW. Potential protective effects of the water-soluble Chinese propolis on experimental ulcerative colitis.J. Tradit. Chin. Med.202343592593337679980
    [Google Scholar]
  92. WangS. GaoS. YeW. LiY. LuanJ. LvX. The emerging importance role of m6A modification in liver disease.Biomed. Pharmacother.202316211466910.1016/j.biopha.2023.11466937037093
    [Google Scholar]
  93. ChengL. WangH. WangZ. HuangH. ZhuoD. LinJ. Leflunomide inhibits proliferation and induces apoptosis via suppressing autophagy and PI3K/Akt signaling pathway in human bladder cancer cells.Drug Des. Devel. Ther.2020141897190810.2147/DDDT.S25262632546957
    [Google Scholar]
  94. TaoZ.S. LiT.L. WeiS. Silymarin prevents iron overload induced bone loss by inhibiting oxidative stress in an ovariectomized animal model.Chem. Biol. Interact.202236611016810.1016/j.cbi.2022.11016836087815
    [Google Scholar]
  95. HeX. LiuG. ChenX. WangY. LiuR. WangC. HuangY. ShenJ. JiaY. Pharmacokinetic and pharmacodynamic interactions between henagliflozin, a novel selective SGLT-2 inhibitor, and warfarin in healthy chinese subjects.Clin. Ther.202345765566110.1016/j.clinthera.2023.06.00237451912
    [Google Scholar]
  96. LiangD. ShenJ. JiaY. DaiM. LiX. ZhouL. WangW. YangB. ShaoJ. JiangY. XieH. SunH. Pharmacokinetic properties of S-oxiracetam after single and multiple intravenous infusions in healthy volunteers.Eur. J. Drug Metab. Pharmacokinet.202146679380510.1007/s13318‑021‑00718‑934549388
    [Google Scholar]
  97. YaoL. YanD. JiangB. XueQ. ChenX. HuangQ. QiL. TangD. ChenX. LiuJ. Plumbagin is a novel GPX4 protein degrader that induces apoptosis in hepatocellular carcinoma cells.Free Radic. Biol. Med.202320311010.1016/j.freeradbiomed.2023.03.26337011699
    [Google Scholar]
  98. SongA. DingT. WeiN. YangJ. MaM. ZhengS. JinH. Schisandrin B induces HepG2 cells pyroptosis by activating NK cells mediated anti-tumor immunity.Toxicol. Appl. Pharmacol.202347211657410.1016/j.taap.2023.11657437271225
    [Google Scholar]
  99. HuangY. LiuR. WangY. LiuG. WangC. ChenX. JiaY. ShenJ. Evaluation of pharmacokinetic interactions between the new SGLT2 inhibitor SHR3824 and valsartan in healthy chinese volunteers.Clin. Ther.202244794595610.1016/j.clinthera.2022.06.00135778161
    [Google Scholar]
  100. DingY. ChenX. LiuC. GeW. WangQ. HaoX. WangM. ChenY. ZhangQ. Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells.J. Hematol. Oncol.20211411910.1186/s13045‑020‑01016‑833472669
    [Google Scholar]
  101. TaoZ.S. ZhouW.S. XuH.G. YangM. Simvastatin can enhance the osseointegration of titanium rods in ovariectomized rats maintenance treatment with valproic acid.Biomed. Pharmacother.202013211074510.1016/j.biopha.2020.11074533068938
    [Google Scholar]
  102. WangZ. TangT. WangS. CaiT. TaoH. ZhangQ. QiS. QiZ. Aloin inhibits the proliferation and migration of gastric cancer cells by regulating NOX2-ROS-mediated pro-survival signal pathways.Drug Des. Devel. Ther.20201414515510.2147/DDDT.S21924732021099
    [Google Scholar]
  103. ZhuJ.M. ChenC. KongM. ZhuL. LiY.L. ZhangJ.F. YuZ.P. XuS.S. KongL.Y. LuoJ.G. Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer.Eur. J. Med. Chem.202326111582910.1016/j.ejmech.2023.11582937801824
    [Google Scholar]
  104. HassanniaB. WiernickiB. IngoldI. QuF. Van HerckS. TyurinaY.Y. BayırH. AbhariB.A. AngeliJ.P.F. ChoiS.M. MeulE. HeyninckK. DeclerckK. ChirumamillaC.S. Lahtela-KakkonenM. Van CampG. KryskoD.V. EkertP.G. FuldaS. De GeestB.G. ConradM. KaganV.E. Vanden BergheW. VandenabeeleP. Vanden BergheT. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma.J. Clin. Invest.201812883341335510.1172/JCI9903229939160
    [Google Scholar]
  105. WangX. ShenC. WangX. TangJ. WuZ. HuangY. ShaoW. GengK. XieH. PuZ. Schisandrin protects against ulcerative colitis by inhibiting the SGK1/NLRP3 signaling pathway and reshaping gut microbiota in mice.Chin. Med.202318111210.1186/s13020‑023‑00815‑837674245
    [Google Scholar]
  106. ChenY. WangS. HuQ. ZhouL. Self-emulsifying system co-loaded with paclitaxel and coix seed oil deeply penetrated to enhance efficacy in cervical cancer.Curr. Drug Deliv.202320791992610.2174/156720181966622062809423935762559
    [Google Scholar]
  107. XingY. LiuB. WanS. ChengY. ZhouS. SunY. YaoX. HuaQ. MengX. ChengJ. ZhongM. ZhangY. LvK. KongX.A. SGLT2 inhibitor dapagliflozin alleviates diabetic cardiomyopathy by suppressing high glucose-induced oxidative stress in vivo and in vitro.Front. Pharmacol.20211270817710.3389/fphar.2021.70817734322029
    [Google Scholar]
  108. SunS. LiS. DuY. WuC. ZhangM. LiJ. ZhangX. Anti-inflammatory effects of the root, stem and leaf extracts of Chloranthus serratus on adjuvant-induced arthritis in rats.Pharm. Biol.202058152853710.1080/13880209.2020.176715932503379
    [Google Scholar]
  109. ZhouC. YuT. ZhuR. LuJ. OuyangX. ZhangZ. ChenQ. LiJ. CuiJ. JiangF. JinK.Y. SarapultsevA. LiF. ZhangG. LuoS. HuD. Timosaponin AIII promotes non-small-cell lung cancer ferroptosis through targeting and facilitating HSP90 mediated GPX4 ubiquitination and degradation.Int. J. Biol. Sci.20231951471148910.7150/ijbs.7797937056925
    [Google Scholar]
  110. DingD. ShenX. YuL. ZhengY. LiuY. WangW. LiuL. ZhaoZ. NianS. LiuL. Timosaponin BII inhibits TGF ‐β mediated epithelial‐mesenchymal transition through Smad‐dependent pathway during pulmonary fibrosis.Phytother. Res.20233772787279910.1002/ptr.777436807664
    [Google Scholar]
  111. HaoJ. BeiJ. LiZ. HanM. MaB. MaP. ZhouX. Qing’e pill inhibits osteoblast ferroptosis via ATM serine/threonine kinase (ATM) and the PI3K/AKT pathway in primary osteoporosis.Front. Pharmacol.20221390210210.3389/fphar.2022.90210235865965
    [Google Scholar]
  112. LuoT. ZhengQ. ShaoL. MaT. MaoL. WangM. Intracellular delivery of glutathione peroxidase degrader induces ferroptosis in vivo.Angew. Chem. Int. Ed.20226139e20220627710.1002/anie.20220627735924720
    [Google Scholar]
  113. WangC. ZhengC. WangH. ShuiS. JinH. LiuG. XuF. LiuZ. ZhangL. SunD. XuP. Dual degradation mechanism of GPX4 degrader in induction of ferroptosis exerting anti-resistant tumor effect.Eur. J. Med. Chem.202324711507210.1016/j.ejmech.2022.11507236603510
    [Google Scholar]
  114. WangZ. XiaY. WangY. ZhuR. LiH. LiuY. ShenN. The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma.Cell Death Dis.2023141069510.1038/s41419‑023‑06222‑z37872147
    [Google Scholar]
  115. CaiM. MaF. HuC. LiH. CaoF. LiY. DongJ. QinJ.J. Design and synthesis of proteolysis-targeting chimeras (PROTACs) as degraders of glutathione peroxidase 4.Bioorg. Med. Chem.20239011735210.1016/j.bmc.2023.11735237257255
    [Google Scholar]
  116. NiuF. YangR. FengH. LiuY. LiuR. MaB.A. GPX4 non-enzymatic domain and MDM2 targeting peptide PROTAC for acute lymphoid leukemia therapy through ferroptosis induction.Biochem. Biophys. Res. Commun.202368414912510.1016/j.bbrc.2023.14912537897912
    [Google Scholar]
  117. SongH. LiangJ. GuoY. LiuY. SaK. YanG. XuW. XuW. ChenL. LiH. A potent GPX4 degrader to induce ferroptosis in HT1080 cells.Eur. J. Med. Chem.202426511611010.1016/j.ejmech.2023.11611038194774
    [Google Scholar]
  118. WangH. WangC. LiB. ZhengC. LiuG. LiuZ. ZhangL. XuP. Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells.Eur. J. Med. Chem.202325411534310.1016/j.ejmech.2023.11534337087895
    [Google Scholar]
  119. ZhengC. WangC. SunD. WangH. LiB. LiuG. LiuZ. ZhangL. XuP. Structure-activity relationship study of RSL3-based GPX4 degraders and its potential noncovalent optimization.Eur. J. Med. Chem.202325511539310.1016/j.ejmech.2023.11539337098297
    [Google Scholar]
  120. LiJ. LiuJ. ZhouZ. WuR. ChenX. YuC. StockwellB. KroemerG. KangR. TangD. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.Sci. Transl. Med.202315720eadg304910.1126/scitranslmed.adg304937910602
    [Google Scholar]
  121. ZhangJ. ZhouW. ChenY. WangY. GuoZ. HuW. LiY. HanX. SiS. Small molecules targeting Pin1 as potent anticancer drugs.Front. Pharmacol.202314107303710.3389/fphar.2023.107303737050909
    [Google Scholar]
  122. LiuS. ZhaoX. ShuiS. WangB. CuiY. DongS. YuwenT. LiuG. PDTAC: Targeted photodegradation of GPX4 triggers ferroptosis and potent antitumor immunity.J. Med. Chem.20226518121761218710.1021/acs.jmedchem.2c0085536066386
    [Google Scholar]
  123. HofmansS. BergheT.V. DevisscherL. HassanniaB. LyssensS. JoossensJ. Van Der VekenP. VandenabeeleP. AugustynsK. Novel ferroptosis inhibitors with improved potency and ADME properties.J. Med. Chem.20165952041205310.1021/acs.jmedchem.5b0164126696014
    [Google Scholar]
  124. HuS. SechiM. SinghP.K. DaiL. McCannS. SunD. LjungmanM. NeamatiN. A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen species.J. Med. Chem.202063179838985510.1021/acs.jmedchem.0c0101632809827
    [Google Scholar]
  125. WangH. ChenY. WangL. LiuQ. YangS. WangC. Advancing herbal medicine: Enhancing product quality and safety through robust quality control practices.Front. Pharmacol.202314126517810.3389/fphar.2023.126517837818188
    [Google Scholar]
  126. ZhouH.H. ChenX. CaiL.Y. NanX.W. ChenJ.H. ChenX.X. YangY. XingZ.H. WeiM.N. LiY. WangS.T. LiuK. ShiZ. YanX.J. Erastin reverses ABCB1-mediated docetaxel resistance in ovarian cancer.Front. Oncol.20199139810.3389/fonc.2019.0139831921655
    [Google Scholar]
  127. ZhangH. LiY. YangR. XiaoL. DongS. LinJ. LiuG. ShanH. Erastin inhibits porcine epidemic diarrhea virus replication in Vero cells.Front. Cell. Infect. Microbiol.202313114217310.3389/fcimb.2023.114217336936772
    [Google Scholar]
  128. ShimadaK. SkoutaR. KaplanA. YangW.S. HayanoM. DixonS.J. BrownL.M. ValenzuelaC.A. WolpawA.J. StockwellB.R. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.Nat. Chem. Biol.201612749750310.1038/nchembio.207927159577
    [Google Scholar]
  129. ArmentaD.A. DixonS.J. Investigating nonapoptotic cell death using chemical biology approaches.Cell Chem. Biol.202027437638610.1016/j.chembiol.2020.03.00532220334
    [Google Scholar]
  130. NguyenK.A. ConilhL. FalsonP. DumontetC. BoumendjelA. The first ADC bearing the ferroptosis inducer RSL3 as a payload with conservation of the fragile electrophilic warhead.Eur. J. Med. Chem.202224411486310.1016/j.ejmech.2022.11486336334452
    [Google Scholar]
  131. HuQ. ZhuW. DuJ. LongS. SunW. FanJ. PengX. A near-infrared GPX4 fluorescent probe for non-small cell lung cancer imaging.Chem. Commun. (Camb.)202359329429710.1039/D2CC06161A36504123
    [Google Scholar]
  132. WangS. YuH. LiL. ZhangM. FuY. LinZ. LiJ. ZhongF. LiuH. WuY. Fluorescent turn-on probes for visualizing GPx4 levels in live cells and predicting drug sensitivity.Anal. Chem.202395238939894710.1021/acs.analchem.3c0086437256969
    [Google Scholar]
  133. HongH. ZouQ. LiuY. WangS. ShenG. YanX. Supramolecular nanodrugs based on covalent assembly of therapeutic peptides toward in vitro synergistic anticancer therapy.ChemMedChem202116152381238510.1002/cmdc.20210023633908190
    [Google Scholar]
  134. HuangM. ZhangY. GongY. LiangZ. ChenX. NiY. PanX. WuW. ChenJ. HuangZ. SunJ. 8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin.J. Inorg. Biochem.202324811236510.1016/j.jinorgbio.2023.11236537690267
    [Google Scholar]
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  • Article Type:
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Keyword(s): cancer therapy; covalence; Ferroptosis; GPX4 inhibitor; prodrug; selenocysteine
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