Skip to content
2000
Volume 33, Issue 6
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Lung cancer remains one of the most prevalent and lethal malignancies, with poor drug response and high mortality rates. Proteolysis-targeting chimeras (PROTACs) are emerging as a novel therapeutic strategy, leveraging E3 ligases to degrade oncogenic proteins selectively the ubiquitin-proteasome pathway. These degraders offer higher selectivity and bioavailability compared to traditional inhibitors. This review explores how PROTACs eliminate oncogenic proteins in lung cancer and examines the role of E3 ligases in this process. Commonly utilized ligases include Cereblon (CRBN) and Von Hippel-Lindau (VHL), while newer ones, such as MDM2 and Kelch-like ECH-associated protein 1 (KEAP1), are being investigated for therapeutic potential. We discuss key factors in PROTAC design, including ligand selection, linker optimization, and pharmacokinetic properties, which influence tumor specificity and efficacy while minimizing off-target effects. Additionally, we highlight targetable oncogenic drivers in lung cancer, such as KRAS, EGFR, and ALK fusion proteins, and evaluate preclinical and clinical studies that demonstrate PROTACs' potential for overcoming drug resistance. The challenges associated with clinical translation, tumor microenvironment interactions, and E3 ligase selection are also discussed. Finally, we present future perspectives, including expanding the range of E3 ligases, developing multitargeting strategies, and integrating next-generation molecular glue degraders. By offering a comparative analysis of E3 ligase-specific PROTACs, this review underscores the potential of PROTAC technology to advance precision oncology in lung cancer.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673382742250619055201
2025-07-15
2026-02-21

  • From This Site

    /content/journals/cmc/10.2174/0109298673382742250619055201
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
     [Google Scholar]
  2. StewartE.L. TanS.Z. LiuG. TsaoM.S. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations - A review.Transl. Lung Cancer Res.201541678125806347
     [Google Scholar]
  3. Sadique HussainM. GuptaG. GhabouraN. MogladE. Hassan AlmalkiW. AlzareaS.I. KazmiI. AliH. MacLoughlinR. LoebenbergR. DaviesN.M. Kumar SinghS. DuaK. Exosomal ncRNAs in liquid biopsies for lung cancer.Clin. Chim. Acta202556511998310.1016/j.cca.2024.11998339368685
     [Google Scholar]
  4. WuY.L. TsuboiM. HeJ. JohnT. GroheC. MajemM. GoldmanJ.W. LaktionovK. KimS.W. KatoT. VuH.V. LuS. LeeK.Y. AkewanlopC. YuC.J. de MarinisF. BonannoL. DomineM. ShepherdF.A. ZengL. HodgeR. AtasoyA. RukazenkovY. HerbstR.S. Osimertinib in resected EGFR -mutated non–small-cell lung cancer.N. Engl. J. Med.2020383181711172310.1056/NEJMoa202707132955177
     [Google Scholar]
  5. HussainM.S. AfzalO. GuptaG. GoyalA. AlmalkiW.H. KazmiI. AlzareaS.I. Alfawaz AltamimiA.S. KukretiN. ChakrabortyA. SinghS.K. DuaK. Unraveling NEAT1's complex role in lung cancer biology: A comprehensive review.Excli J.202423345238343745
     [Google Scholar]
  6. TangS. QinC. HuH. LiuT. HeY. GuoH. YanH. ZhangJ. TangS. ZhouH. Immune checkpoint inhibitors in non-small cell lung cancer: Progress, challenges, and prospects.Cells202211332010.3390/cells1103032035159131
     [Google Scholar]
  7. LaiA.C. CrewsC.M. Induced protein degradation: An emerging drug discovery paradigm.Nat. Rev. Drug Discov.201716210111410.1038/nrd.2016.21127885283
     [Google Scholar]
  8. PetterssonM. CrewsC.M. PROteolysis Targeting Chimeras (PROTACs) — Past, present and future.Drug Discov. Today. Technol.201931152710.1016/j.ddtec.2019.01.00231200855
     [Google Scholar]
  9. AnS. FuL. Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs.EBioMedicine20183655356210.1016/j.ebiom.2018.09.00530224312
     [Google Scholar]
  10. BurslemG.M. CrewsC.M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery.Cell2020181110211410.1016/j.cell.2019.11.03131955850
     [Google Scholar]
  11. MetzgerM.B. HristovaV.A. WeissmanA.M. HECT and RING finger families of E3 ubiquitin ligases at a glance.J. Cell Sci.2012125353153710.1242/jcs.09177722389392
     [Google Scholar]
  12. GaddM.S. TestaA. LucasX. ChanK.H. ChenW. LamontD.J. ZengerleM. CiulliA. Structural basis of PROTAC cooperative recognition for selective protein degradation.Nat. Chem. Biol.201713551452110.1038/nchembio.232928288108
     [Google Scholar]
  13. BékésM. LangleyD.R. CrewsC.M. PROTAC targeted protein degraders: The past is prologue.Nat. Rev. Drug Discov.202221318120010.1038/s41573‑021‑00371‑635042991
     [Google Scholar]
  14. DengL. MengT. ChenL. WeiW. WangP. The role of ubiquitination in tumorigenesis and targeted drug discovery.Signal Transduct. Target. Ther.2020511110.1038/s41392‑020‑0107‑032296023
     [Google Scholar]
  15. VassilevL.T. VuB.T. GravesB. CarvajalD. PodlaskiF. FilipovicZ. KongN. KammlottU. LukacsC. KleinC. FotouhiN. LiuE.A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science2004303565984484810.1126/science.109247214704432
     [Google Scholar]
  16. ItohY. IshikawaM. NaitoM. HashimotoY. Protein knockdown using methyl bestatin-ligand hybrid molecules: Design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins.J. Am. Chem. Soc.2010132165820582610.1021/ja100691p20369832
     [Google Scholar]
  17. BuckleyD.L. Van MolleI. GareissP.C. TaeH.S. MichelJ. NoblinD.J. JorgensenW.L. CiulliA. CrewsC.M. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction.J. Am. Chem. Soc.2012134104465446810.1021/ja209924v22369643
     [Google Scholar]
  18. Lopez-GironaA. MendyD. ItoT. MillerK. GandhiA.K. KangJ. KarasawaS. CarmelG. JacksonP. AbbasianM. MahmoudiA. CathersB. RychakE. GaidarovaS. ChenR. SchaferP.H. HandaH. DanielT.O. EvansJ.F. ChopraR. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.Leukemia201226112326233510.1038/leu.2012.11922552008
     [Google Scholar]
  19. ChamberlainP.P. HamannL.G. Development of targeted protein degradation therapeutics.Nat. Chem. Biol.2019151093794410.1038/s41589‑019‑0362‑y31527835
     [Google Scholar]
  20. SampsonC. WangQ. OtkurW. ZhaoH. LuY. LiuX. PiaoH. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy.Clin. Transl. Med.2023133e120410.1002/ctm2.120436881608
     [Google Scholar]
  21. GuS. CuiD. ChenX. XiongX. ZhaoY. PROTACs: An emerging targeting technique for protein degradation in drug discovery.BioEssays2018404170024710.1002/bies.20170024729473971
     [Google Scholar]
  22. EletrZ.M. HuangD.T. DudaD.M. SchulmanB.A. KuhlmanB. E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer.Nat. Struct. Mol. Biol.2005121093393410.1038/nsmb98416142244
     [Google Scholar]
  23. ZhengN. ShabekN. Ubiquitin ligases: Structure, function, and regulation.Annu. Rev. Biochem.201786112915710.1146/annurev‑biochem‑060815‑01492228375744
     [Google Scholar]
  24. AravindL. KooninE.V. The U box is a modified RING finger — A common domain in ubiquitination.Curr. Biol.2000104R132R13410.1016/S0960‑9822(00)00398‑510704423
     [Google Scholar]
  25. JiangJ. BallingerC.A. WuY. DaiQ. CyrD.M. HöhfeldJ. PattersonC. CHIP is a U-box-dependent E3 ubiquitin ligase: Identification of Hsc70 as a target for ubiquitylation.J. Biol. Chem.200127646429384294410.1074/jbc.M10196820011557750
     [Google Scholar]
  26. RotinD. KumarS. Physiological functions of the HECT family of ubiquitin ligases.Nat. Rev. Mol. Cell Biol.200910639840910.1038/nrm269019436320
     [Google Scholar]
  27. WeberJ. PoloS. MasperoE. HECT E3 ligases: A tale with multiple facets.Front. Physiol.20191037010.3389/fphys.2019.0037031001145
     [Google Scholar]
  28. HuangL. KinnucanE. WangG. BeaudenonS. HowleyP.M. HuibregtseJ.M. PavletichN.P. Structure of an E6AP-UbcH7 complex: Insights into ubiquitination by the E2-E3 enzyme cascade.Science199928654431321132610.1126/science.286.5443.132110558980
     [Google Scholar]
  29. MarínI. LucasJ.I. GradillaA.C. FerrúsA. Parkin and relatives: The RBR family of ubiquitin ligases.Physiol. Genomics200417325326310.1152/physiolgenomics.00226.200315152079
     [Google Scholar]
  30. WenzelD.M. LissounovA. BrzovicP.S. KlevitR.E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids.Nature2011474734910510810.1038/nature0996621532592
     [Google Scholar]
  31. BondesonD.P. MaresA. SmithI.E.D. KoE. CamposS. MiahA.H. MulhollandK.E. RoutlyN. BuckleyD.L. GustafsonJ.L. ZinnN. GrandiP. ShimamuraS. BergaminiG. Faelth-SavitskiM. BantscheffM. CoxC. GordonD.A. WillardR.R. FlanaganJ.J. CasillasL.N. VottaB.J. den BestenW. FammK. KruidenierL. CarterP.S. HarlingJ.D. ChurcherI. CrewsC.M. Catalytic in vivo protein knockdown by small-molecule PROTACs.Nat. Chem. Biol.201511861161710.1038/nchembio.185826075522
     [Google Scholar]
  32. NguyenK.M. BusinoL. Targeting the E3 ubiquitin ligases DCAF15 and cereblon for cancer therapy.Semin. Cancer Biol.202067Pt 2536010.1016/j.semcancer.2020.03.00732200025
     [Google Scholar]
  33. JinJ. WuY. ChenJ. ShenY. ZhangL. ZhangH. ChenL. YuanH. ChenH. ZhangW. LuanX. The peptide PROTAC modality: A novel strategy for targeted protein ubiquitination.Theranostics20201022101411015310.7150/thno.4698532929339
     [Google Scholar]
  34. Hojjat-FarsangiM. Small-molecule inhibitors of the receptor tyrosine kinases: Promising tools for targeted cancer therapies.Int. J. Mol. Sci.2014158137681380110.3390/ijms15081376825110867
     [Google Scholar]
  35. PassaroA. JänneP.A. PetersS. Antibody-drug conjugates in lung cancer: Recent advances and implementing strategies.J. Clin. Oncol.202341213747376110.1200/JCO.23.0001337224424
     [Google Scholar]
  36. BurslemG.M. CrewsC.M. Small-molecule modulation of protein homeostasis.Chem. Rev.201711717112691130110.1021/acs.chemrev.7b0007728777566
     [Google Scholar]
  37. HedeK. Blocking cancer with RNA interference moves toward the clinic.J. Natl. Cancer Inst.200597962662810.1093/jnci/97.9.62615870429
     [Google Scholar]
  38. LiJ.W. ZhengG. KayeF.J. WuL. PROTAC therapy as a new targeted therapy for lung cancer.Mol. Ther.202331364765610.1016/j.ymthe.2022.11.01136415148
     [Google Scholar]
  39. NaitoM. OhokaN. ShibataN. TsukumoY. Targeted protein degradation by chimeric small molecules, PROTACs and SNIPERs.Front Chem.2019784910.3389/fchem.2019.0084931921772
     [Google Scholar]
  40. LiD. DengY. WenG. WangL. ShiX. ChenS. ChenR. Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.Int. Immunopharmacol.202413211199110.1016/j.intimp.2024.11199138581996
     [Google Scholar]
  41. LiuJ. ChenH. KaniskanH.Ü. XieL. ChenX. JinJ. WeiW. TF-PROTACs enable targeted degradation of transcription factors.J. Am. Chem. Soc.2021143238902891010.1021/jacs.1c0385234100597
     [Google Scholar]
  42. KhanS. WiegandJ. ZhangP. HuW. ThummuriD. BudamaguntaV. HuaN. JinL. AllegraC.J. KopetzS.E. Zajac-KayeM. KayeF.J. ZhengG. ZhouD. BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers.J. Hematol. Oncol.20221512310.1186/s13045‑022‑01241‑335260176
     [Google Scholar]
  43. YimJ. ParkJ. KimG. LeeH.H. ChungJ.S. JoA. KohM. ParkJ. Conditional PROTAC: Recent strategies for modulating targeted protein degradation.ChemMedChem20241922e20240032610.1002/cmdc.20240032638993102
     [Google Scholar]
  44. KhanS. HeY. ZhangX. YuanY. PuS. KongQ. ZhengG. ZhouD. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics.Oncogene202039264909492410.1038/s41388‑020‑1336‑y32475992
     [Google Scholar]
  45. GeorgeA.J. HoffizY.C. CharlesA.J. ZhuY. MabbA.M. A comprehensive atlas of E3 ubiquitin ligase mutations in neurological disorders.Front. Genet.201892910.3389/fgene.2018.0002929491882
     [Google Scholar]
  46. SenftD. QiJ. RonaiZ.A. Ubiquitin ligases in oncogenic transformation and cancer therapy.Nat. Rev. Cancer2018182698810.1038/nrc.2017.10529242641
     [Google Scholar]
  47. YangD. ChengD. TuQ. YangH. SunB. YanL. DaiH. LuoJ. MaoB. CaoY. YuX. JiangH. ZhaoX. HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53.Theranostics20188133517352910.7150/thno.2440130026863
     [Google Scholar]
  48. AmodioN. ScrimaM. PalaiaL. SalmanA.N. QuintieroA. FrancoR. BottiG. PirozziP. RoccoG. De RosaN. VigliettoG. Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small- cell lung carcinomas.Am. J. Pathol.201017752622263410.2353/ajpath.2010.09107520889565
     [Google Scholar]
  49. GuJ. MaoW. RenW. XuF. ZhuQ. LuC. LinZ. ZhangZ. ChuY. LiuR. GeD. Ubiquitin-protein ligase E3C maintains non-small-cell lung cancer stemness by targeting AHNAK-p53 complex.Cancer Lett.201944312513410.1016/j.canlet.2018.11.02930503554
     [Google Scholar]
  50. LuX. HuangX. XuH. LuS. YouS. XuJ. ZhanQ. DongC. ZhangN. ZhangY. CaoL. ZhangX. ZhangN. ZhangL. The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia.Cell Death Discov.20228142110.1038/s41420‑022‑01209‑936257929
     [Google Scholar]
  51. ShuklaS. AllamU.S. AhsanA. ChenG. KrishnamurthyP.M. MarshK. RumschlagM. ShankarS. WhiteheadC. SchipperM. BasrurV. SouthworthD.R. ChinnaiyanA.M. RehemtullaA. BeerD.G. LawrenceT.S. NyatiM.K. RayD. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation.Neoplasia2014162115W510.1593/neo.1418424709419
     [Google Scholar]
  52. DuanH. LeiZ. XuF. PanT. LuD. DingP. ZhuC. PanC. ZhangS. PARK2 suppresses proliferation and tumorigenicity in non-small cell lung cancer.Front. Oncol.2019979010.3389/fonc.2019.0079031508359
     [Google Scholar]
  53. WangS. XuL. CheX. LiC. XuL. HouK. FanY. WenT. QuX. LiuY. E3 ubiquitin ligases Cbl-b and c-Cbl downregulate PD-L1 in EGFR wild-type non-small cell lung cancer.FEBS Lett.2018592462163010.1002/1873‑3468.1298529364514
     [Google Scholar]
  54. RorsmanC. TsioumpekouM. HeldinC.H. LennartssonJ. The ubiquitin ligases c-Cbl and Cbl-b negatively regulate platelet-derived growth factor (PDGF) BB-induced chemotaxis by affecting PDGF receptor β (PDGFRβ) internalization and signaling.J. Biol. Chem.201629122116081161810.1074/jbc.M115.70581427048651
     [Google Scholar]
  55. HongS.Y. KaoY.R. LeeT.C. WuC.W. Upregulation of E3 ubiquitin ligase CBLC enhances EGFR dysregulation and signaling in lung adenocarcinoma.Cancer Res.201878174984499610.1158/0008‑5472.CAN‑17‑385829945960
     [Google Scholar]
  56. YuX. Minter-DykhouseK. MalureanuL. ZhaoW.M. ZhangD. MerkleC.J. WardI.M. SayaH. FangG. van DeursenJ. ChenJ. Chfr is required for tumor suppression and Aurora A regulation.Nat. Genet.200537440140610.1038/ng153815793587
     [Google Scholar]
  57. LiuZ. WuY. TaoZ. MaL. E3 ubiquitin ligase Hakai regulates cell growth and invasion, and increases the chemosensitivity to cisplatin in non-small-cell lung cancer cells.Int. J. Mol. Med.20184221145115110.3892/ijmm.2018.368329786107
     [Google Scholar]
  58. LiuL. YuL. ZengC. LongH. DuanG. YinG. DaiX. LinZ. E3 ubiquitin ligase HRD1 promotes lung tumorigenesis by promoting sirtuin 2 ubiquitination and degradation.Mol. Cell. Biol.2020407e00257-1910.1128/MCB.00257‑1931932479
     [Google Scholar]
  59. HauptY. MayaR. KazazA. OrenM. Mdm2 promotes the rapid degradation of p53.Nature1997387663029629910.1038/387296a09153395
     [Google Scholar]
  60. LiK. ZhengX. TangH. ZangY.S. ZengC. LiuX. ShenY. PangY. WangS. XieF. LuX. LuoY. LiZ. BiW. JiaX. HuangT. WeiR. HuangK. ChenZ. ZhuQ. HeY. ZhangM. GuZ. XiaoY. ZhangX. FletcherJ.A. WangY. E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer.J. Exp. Med.20212188e2021015110.1084/jem.2021015134143182
     [Google Scholar]
  61. HattoriT. IsobeT. AbeK. KikuchiH. KitagawaK. OdaT. UchidaC. KitagawaM. Pirh2 promotes ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1.Cancer Res.20076722107891079510.1158/0008‑5472.CAN‑07‑203318006823
     [Google Scholar]
  62. WuX.T. WangY.H. CaiX.Y. DongY. CuiQ. ZhouY.N. YangX.W. LuW.F. ZhangM. RNF115 promotes lung adenocarcinoma through Wnt/β-catenin pathway activation by mediating APC ubiquitination.Cancer Metab.202191710.1186/s40170‑021‑00243‑y33509267
     [Google Scholar]
  63. CallowM.G. TranH. PhuL. LauT. LeeJ. SandovalW.N. LiuP.S. BheddahS. TaoJ. LillJ.R. HongoJ.A. DavisD. KirkpatrickD.S. PolakisP. CostaM. Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling.PLoS One201167e2259510.1371/journal.pone.002259521799911
     [Google Scholar]
  64. DingY. LuY. XieX. CaoL. ZhengS. Ring finger protein 180 suppresses cell proliferation and energy metabolism of non-small cell lung cancer through downregulating C-myc.World J. Surg. Oncol.202220116210.1186/s12957‑022‑02599‑x35598017
     [Google Scholar]
  65. NakayamaK. FrewI.J. HagensenM. SkalsM. HabelhahH. BhoumikA. KadoyaT. Erdjument-BromageH. TempstP. FrappellP.B. BowtellD.D. RonaiZ. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia.Cell2004117794195210.1016/j.cell.2004.06.00115210114
     [Google Scholar]
  66. WangQ. GaoG. ZhangT. YaoK. ChenH. ParkM.H. YamamotoH. WangK. MaW. MalakhovaM. BodeA.M. DongZ. TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non–small cell lung carcinogenesis.Cancer Res.201878143982399410.1158/0008‑5472.CAN‑18‑042929748372
     [Google Scholar]
  67. LinaresJ.F. DuranA. YajimaT. PasparakisM. MoscatJ. Diaz-MecoM.T. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells.Mol. Cell201351328329610.1016/j.molcel.2013.06.02023911927
     [Google Scholar]
  68. LiangM. WangL. SunZ. ChenX. WangH. QinL. ZhaoW. GengB. E3 ligase TRIM15 facilitates non-small cell lung cancer progression through mediating Keap1-Nrf2 signaling pathway.Cell Commun. Signal.20222016210.1186/s12964‑022‑00875‑735534896
     [Google Scholar]
  69. AlltonK. JainA.K. HerzH.M. TsaiW.W. JungS.Y. QinJ. BergmannA. JohnsonR.L. BartonM.C. Trim24 targets endogenous p53 for degradation.Proc. Natl. Acad. Sci. USA200910628116121161610.1073/pnas.081317710619556538
     [Google Scholar]
  70. HeY. ZhouX. JiangS. ZhangZ. CaoB. LiuJ. ZengY. ZhaoJ. MaoX. TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer.Acta Pharmacol. Sin.202243368169110.1038/s41401‑021‑00662‑z33931764
     [Google Scholar]
  71. BornsteinG. BloomJ. Sitry-ShevahD. NakayamaK. PaganoM. HershkoA. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase.J. Biol. Chem.200327828257522575710.1074/jbc.M30177420012730199
     [Google Scholar]
  72. MorizaneY. HondaR. FukamiK. YasudaH. X-linked inhibitor of apoptosis functions as ubiquitin ligase toward mature caspase-9 and cytosolic Smac/DIABLO.J. Biochem.2005137212513210.1093/jb/mvi02915749826
     [Google Scholar]
  73. ShiY. WangX. XuZ. HeY. GuoC. HeL. HuanC. CaiC. HuangJ. ZhangJ. LiY. ZengC. ZhangX. WangL. KeY. ChengH. PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.J. Biol. Chem.202029540137981381110.1074/jbc.RA120.01497632737199
     [Google Scholar]
  74. BurslemG.M. OttisP. Jaime-FigueroaS. MorganA. CrommP.M. ToureM. CrewsC.M. Efficient synthesis of immunomodulatory drug analogues enables exploration of structure–degradation relationships.ChemMedChem201813151508151210.1002/cmdc.20180027129870139
     [Google Scholar]
  75. SakamotoK.M. KimK.B. KumagaiA. MercurioF. CrewsC.M. DeshaiesR.J. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation.Proc. Natl. Acad. Sci. USA200198158554855910.1073/pnas.14123079811438690
     [Google Scholar]
  76. SchneeklothJ.S.Jr FonsecaF.N. KoldobskiyM. MandalA. DeshaiesR. SakamotoK. CrewsC.M. Chemical genetic control of protein levels: Selective in vivo targeted degradation.J. Am. Chem. Soc.2004126123748375410.1021/ja039025z15038727
     [Google Scholar]
  77. SunX. GaoH. YangY. HeM. WuY. SongY. TongY. RaoY. PROTACs: Great opportunities for academia and industry.Signal Transduct. Target. Ther.2019416410.1038/s41392‑019‑0101‑631885879
     [Google Scholar]
  78. SchneeklothA.R. PucheaultM. TaeH.S. CrewsC.M. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.Bioorg. Med. Chem. Lett.200818225904590810.1016/j.bmcl.2008.07.11418752944
     [Google Scholar]
  79. SpradlinJ.N. HuX. WardC.C. BrittainS.M. JonesM.D. OuL. ToM. ProudfootA. OrnelasE. WoldegiorgisM. OlzmannJ.A. BussiereD.E. ThomasJ.R. TallaricoJ.A. McKennaJ.M. SchirleM. MaimoneT.J. NomuraD.K. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation.Nat. Chem. Biol.201915774775510.1038/s41589‑019‑0304‑831209351
     [Google Scholar]
  80. ZhangX. CrowleyV.M. WucherpfennigT.G. DixM.M. CravattB.F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16.Nat. Chem. Biol.201915773774610.1038/s41589‑019‑0279‑531209349
     [Google Scholar]
  81. TongB. LuoM. XieY. SpradlinJ.N. TallaricoJ.A. McKennaJ.M. SchirleM. MaimoneT.J. NomuraD.K. Bardoxolone conjugation enables targeted protein degradation of BRD4.Sci. Rep.20201011554310.1038/s41598‑020‑72491‑932968148
     [Google Scholar]
  82. ChamberlainP.P. Lopez-GironaA. MillerK. CarmelG. PagariganB. Chie-LeonB. RychakE. CorralL.G. RenY.J. WangM. RileyM. DelkerS.L. ItoT. AndoH. MoriT. HiranoY. HandaH. HakoshimaT. DanielT.O. CathersB.E. Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs.Nat. Struct. Mol. Biol.201421980380910.1038/nsmb.287425108355
     [Google Scholar]
  83. ZhuY.X. BraggioE. ShiC.X. BruinsL.A. SchmidtJ.E. Van WierS. ChangX.B. BjorklundC.C. FonsecaR. BergsagelP.L. OrlowskiR.Z. StewartA.K. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.Blood2011118184771477910.1182/blood‑2011‑05‑35606321860026
     [Google Scholar]
  84. Noblejas-LópezM.M. Tébar-GarcíaD. López-RosaR. Alcaraz-SanabriaA. Cristóbal-CuetoP. Pinedo-SerranoA. Rivas-GarcíaL. Galán-MoyaE.M. TACkling cancer by targeting selective protein degradation.Pharmaceutics20231510244210.3390/pharmaceutics1510244237896202
     [Google Scholar]
  85. ThapaR. BhatA.A. GuptaG. Renuka JyothiS. KaurI. KumarS. SharmaN. PrasadG.V.S. PramanikA. AliH. CRBN-PROTACs in cancer therapy: From mechanistic insights to clinical applications.Chem. Biol. Drug Des.20241045e7000910.1111/cbdd.7000939496477
     [Google Scholar]
  86. QuX. LiuH. SongX. SunN. ZhongH. QiuX. YangX. JiangB. Effective degradation of EGFRL858R+T790M mutant proteins by CRBN-based PROTACs through both proteosome and autophagy/lysosome degradation systems.Eur. J. Med. Chem.202121811332810.1016/j.ejmech.2021.11332833773286
     [Google Scholar]
  87. BurslemG.M. SmithB.E. LaiA.C. Jaime-FigueroaS. McQuaidD.C. BondesonD.P. ToureM. DongH. QianY. WangJ. CrewA.P. HinesJ. CrewsC.M. The advantages of targeted protein degradation over inhibition: An RTK case study.Cell Chem. Biol.20182516777.e310.1016/j.chembiol.2017.09.00929129716
     [Google Scholar]
  88. DuY. ChenY. WangY. ChenJ. LuX. ZhangL. LiY. WangZ. YeG. ZhangG. HJM-561, a potent, selective, and orally bioavailable EGFR PROTAC that overcomes osimertinib-resistant EGFR triple mutations.Mol. Cancer Ther.20222171060106610.1158/1535‑7163.MCT‑21‑083535499406
     [Google Scholar]
  89. ShiS. DuY. HuangL. CuiJ. NiuJ. XuY. ZhuQ. Discovery of novel potent covalent inhibitor-based EGFR degrader with excellent in vivo efficacy.Bioorg. Chem.202212010560510.1016/j.bioorg.2022.10560535081479
     [Google Scholar]
  90. ShenJ. ChenL. LiuJ. LiA. ZhengL. ChenS. LiY. EGFR degraders in non-small-cell lung cancer: Breakthrough and unresolved issue.Chem. Biol. Drug Des.20241034e1451710.1111/cbdd.1451738610074
     [Google Scholar]
  91. ZhangW. LiP. SunS. JiaC. YangN. ZhuangX. ZhengZ. LiS. Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo.Eur. J. Med. Chem.202223811450910.1016/j.ejmech.2022.11450935691176
     [Google Scholar]
  92. ZengM. XiongY. SafaeeN. NowakR.P. DonovanK.A. YuanC.J. NabetB. GeroT.W. FeruF. LiL. GondiS. OmbeletsL.J. QuanC. JänneP.A. KosticM. ScottD.A. WestoverK.D. FischerE.S. GrayN.S. Exploring targeted degradation strategy for oncogenic KRASG12C.Cell Chem. Biol.20202711931.e610.1016/j.chembiol.2019.12.00631883964
     [Google Scholar]
  93. BondM.J. ChuL. NalawanshaD.A. LiK. CrewsC.M. Targeted degradation of oncogenic KRAS G12C by VHL-recruiting PROTACs.ACS Cent. Sci.2020681367137510.1021/acscentsci.0c0041132875077
     [Google Scholar]
  94. HussainM.S. MogladE. AfzalM. BansalP. KaurH. DeorariM. AliH. ShahwanM. Hassan almalkiW. KazmiI. AlzareaS.I. SinghS.K. DuaK. GuptaG. Circular RNAs in the KRAS pathway: Emerging players in cancer progression.Pathol. Res. Pract.202425615525910.1016/j.prp.2024.15525938503004
     [Google Scholar]
  95. PowellC.E. GaoY. TanL. DonovanK.A. NowakR.P. LoehrA. BahcallM. FischerE.S. JänneP.A. GeorgeR.E. GrayN.S. Chemically induced degradation of anaplastic lymphoma kinase (ALK).J. Med. Chem.20186194249425510.1021/acs.jmedchem.7b0165529660984
     [Google Scholar]
  96. LiuJ. ChenH. MaL. HeZ. WangD. LiuY. LinQ. ZhangT. GrayN. KaniskanH.Ü. JinJ. WeiW. Light-induced control of protein destruction by opto-PROTAC.Sci. Adv.202068eaay515410.1126/sciadv.aay515432128407
     [Google Scholar]
  97. RenC. SunN. KongY. QuX. LiuH. ZhongH. SongX. YangX. JiangB. Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib.Eur. J. Med. Chem.202121711333510.1016/j.ejmech.2021.11333533751979
     [Google Scholar]
  98. Czyzyk-KrzeskaM.F. MellerJ. von Hippel–Lindau tumor suppressor: Not only HIF’s executioner.Trends Mol. Med.200410414614910.1016/j.molmed.2004.02.00415162797
     [Google Scholar]
  99. BuckleyD.L. GustafsonJ.L. Van MolleI. RothA.G. TaeH.S. GareissP.C. JorgensenW.L. CiulliA. CrewsC.M. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α.Angew. Chem. Int. Ed.20125146114631146710.1002/anie.20120623123065727
     [Google Scholar]
  100. WangX. FengS. FanJ. LiX. WenQ. LuoN. New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation.Biochem. Pharmacol.201611620020910.1016/j.bcp.2016.07.01727473774
     [Google Scholar]
  101. YangF. WenY. WangC. ZhouY. ZhouY. ZhangZ.M. LiuT. LuX. Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC.Eur. J. Med. Chem.202223011408810.1016/j.ejmech.2021.11408835007863
     [Google Scholar]
  102. ZhouC. FanZ. ZhouZ. LiY. CuiR. LiuC. ZhouG. DiaoX. JiangH. ZhengM. ZhangS. XuT. Discovery of the first-in-class agonist-based SOS1 PROTACs effective in human cancer cells harboring various KRAS mutations.J. Med. Chem.20226553923394210.1021/acs.jmedchem.1c0177435230841
     [Google Scholar]
  103. LavacchiD. MazzoniF. GiacconeG. Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): Current perspectives.Drug Des. Devel. Ther.2019133187319810.2147/DDDT.S19423131564835
     [Google Scholar]
  104. WangM. LuJ. WangM. YangC.Y. WangS. Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein.J. Med. Chem.202063147510752810.1021/acs.jmedchem.0c0047132437146
     [Google Scholar]
  105. LiuJ. XueL. XuX. LuoJ. ZhangS. FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer.Exp. Cell Res.2021408211286810.1016/j.yexcr.2021.11286834648846
     [Google Scholar]
  106. SunY. WangR. SunY. WangL. XueY. WangJ. WuT. YinW. QinQ. SunY. ZhaoD. ChengM. Identification of novel and potent PROTACs targeting FAK for non-small cell lung cancer: Design, synthesis, and biological study.Eur. J. Med. Chem.202223711437310.1016/j.ejmech.2022.11437335486993
     [Google Scholar]
  107. BaiL. ZhouH. XuR. ZhaoY. ChinnaswamyK. McEachernD. ChenJ. YangC.Y. LiuZ. WangM. LiuL. JiangH. WenB. KumarP. MeagherJ.L. SunD. StuckeyJ.A. WangS. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo.Cancer Cell2019365498511.e1710.1016/j.ccell.2019.10.00231715132
     [Google Scholar]
  108. KhanS. ZhangX. LvD. ZhangQ. HeY. ZhangP. LiuX. ThummuriD. YuanY. WiegandJ.S. PeiJ. ZhangW. SharmaA. McCurdyC.R. KuruvillaV.M. BaranN. FerrandoA.A. KimY. RogojinaA. HoughtonP.J. HuangG. HromasR. KonoplevaM. ZhengG. ZhouD. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity.Nat. Med.201925121938194710.1038/s41591‑019‑0668‑z31792461
     [Google Scholar]
  109. DiehlC.J. CiulliA. Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.Chem. Soc. Rev.202251198216825710.1039/D2CS00387B35983982
     [Google Scholar]
  110. LuD. YuX. LinH. ChengR. MonroyE.Y. QiX. WangM.C. WangJ. Applications of covalent chemistry in targeted protein degradation.Chem. Soc. Rev.202251229243926110.1039/D2CS00362G36285735
     [Google Scholar]
  111. TamuraT. KawanoM. HamachiI. Targeted covalent modification strategies for drugging the undruggable targets.Chem. Rev.202512521191125310.1021/acs.chemrev.4c0074539772527
     [Google Scholar]
  112. FuldaS. VucicD. Targeting IAP proteins for therapeutic intervention in cancer.Nat. Rev. Drug Discov.201211210912410.1038/nrd362722293567
     [Google Scholar]
  113. CohenP. TcherpakovM. Will the ubiquitin system furnish as many drug targets as protein kinases?Cell2010143568669310.1016/j.cell.2010.11.01621111230
     [Google Scholar]
  114. OhokaN. OkuhiraK. ItoM. NagaiK. ShibataN. HattoriT. UjikawaO. ShimokawaK. SanoO. KoyamaR. FujitaH. TerataniM. MatsumotoH. ImaedaY. NaraH. ChoN. NaitoM. In vivo knockdown of pathogenic proteins via specific and nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs).J. Biol. Chem.2017292114556457010.1074/jbc.M116.76885328154167
     [Google Scholar]
  115. VarfolomeevE. BlankenshipJ.W. WaysonS.M. FedorovaA.V. KayagakiN. GargP. ZobelK. DynekJ.N. ElliottL.O. WallweberH.J.A. FlygareJ.A. FairbrotherW.J. DeshayesK. DixitV.M. VucicD. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.Cell2007131466968110.1016/j.cell.2007.10.03018022362
     [Google Scholar]
  116. OkuhiraK. DemizuY. HattoriT. OhokaN. ShibataN. Nishimaki-MogamiT. OkudaH. KuriharaM. NaitoM. Development of hybrid small molecules that induce degradation of estrogen receptor‐alpha and necrotic cell death in breast cancer cells.Cancer Sci.2013104111492149810.1111/cas.1227223992566
     [Google Scholar]
  117. CossuF. MilaniM. MastrangeloE. LecisD. Targeting the BIR domains of Inhibitor of Apoptosis (IAP) proteins in cancer treatment.Comput. Struct. Biotechnol. J.20191714215010.1016/j.csbj.2019.01.00930766663
     [Google Scholar]
  118. VucicD. FairbrotherW.J. The inhibitor of apoptosis proteins as therapeutic targets in cancer.Clin. Cancer Res.200713205995600010.1158/1078‑0432.CCR‑07‑072917947460
     [Google Scholar]
  119. ThapaR. GuptaS. GuptaG. BhatA.A. Smriti SinglaM. AliH. SinghS.K. DuaK. KashyapM.K. Epithelial–mesenchymal transition to mitigate age-related progression in lung cancer.Ageing Res. Rev.202410210257610.1016/j.arr.2024.10257639515620
     [Google Scholar]
  120. LevineA.J. p53, the cellular gatekeeper for growth and division.Cell199788332333110.1016/S0092‑8674(00)81871‑19039259
     [Google Scholar]
  121. MichaelD. OrenM. The p53–Mdm2 module and the ubiquitin system.Semin. Cancer Biol.2003131495810.1016/S1044‑579X(02)00099‑812507556
     [Google Scholar]
  122. MomandJ. JungD. WilczynskiS. NilandJ. The MDM2 gene amplification database.Nucleic Acids Res.199826153453345910.1093/nar/26.15.34539671804
     [Google Scholar]
  123. SinghS. SaxenaS. SharmaH. PaudelK.R. ChakrabortyA. MacLoughlinR. OliverB.G. GuptaG. NegiP. SinghS.K. DuaK. Emerging role of tumor suppressing microRNAs as therapeutics in managing non-small cell lung cancer.Pathol. Res. Pract.202425615522210.1016/j.prp.2024.15522238452582
     [Google Scholar]
  124. SunY. ZhaoX. DingN. GaoH. WuY. YangY. ZhaoM. HwangJ. SongY. LiuW. RaoY. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies.Cell Res.201828777978110.1038/s41422‑018‑0055‑129875397
     [Google Scholar]
  125. ZhaoQ. LanT. SuS. RaoY. Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule.Chem. Commun. (Camb.)201955336937210.1039/C8CC07813K30540295
     [Google Scholar]
  126. VicenteA.T.S. SalvadorJ.A.R. MDM2-based proteolysis-targeting chimeras (PROTACs): An innovative drug strategy for cancer treatment.Int. J. Mol. Sci.202223191106810.3390/ijms23191106836232374
     [Google Scholar]
  127. HinesJ. LartigueS. DongH. QianY. CrewsC.M. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53.Cancer Res.201979125126210.1158/0008‑5472.CAN‑18‑291830385614
     [Google Scholar]
  128. QiS.M. DongJ. XuZ.Y. ChengX.D. ZhangW.D. QinJ.J. PROTAC: An effective targeted protein degradation strategy for cancer therapy.Front. Pharmacol.20211269257410.3389/fphar.2021.69257434025443
     [Google Scholar]
  129. SaeidA.B. PaudelK.R. De RubisG. MehndirattaS. KokkinisS. VishwasS. YeungS. GuptaG. SinghS.K. DuaK. Fisetin-loaded nanoemulsion ameliorates lung cancer pathogenesis via downregulating cathepsin-B, galectin-3 and enolase in an in vitro setting.EXCLI J.2024231238124439574963
     [Google Scholar]
  130. YaoY. ZhangQ. LiZ. ZhangH. MDM2: Current research status and prospects of tumor treatment.Cancer Cell Int.202424117010.1186/s12935‑024‑03356‑838741108
     [Google Scholar]
  131. HouH. SunD. ZhangX. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors.Cancer Cell Int.201919121610.1186/s12935‑019‑0937‑431440117
     [Google Scholar]
  132. PaudelK.R. SinghM. De RubisG. KumbharP. MehndirattaS. KokkinisS. El-SherkawiT. GuptaG. SinghS.K. MalikM.Z. MohammedY. OliverB.G. DisouzaJ. PatravaleV. HansbroP.M. DuaK. Computational and biological approaches in repurposing ribavirin for lung cancer treatment: Unveiling antitumorigenic strategies.Life Sci.202435212285910.1016/j.lfs.2024.12285938925223
     [Google Scholar]
  133. SunD. QianH. LiJ. XingP. Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy.J. Biomed. Sci.20243111710.1186/s12929‑024‑01004‑x38281981
     [Google Scholar]
  134. HanT. GoralskiM. GaskillN. CapotaE. KimJ. TingT.C. XieY. WilliamsN.S. NijhawanD. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.Science20173566336eaal375510.1126/science.aal375528302793
     [Google Scholar]
  135. MaqboolM. HussainM.S. BishtA.S. KumariA. KamranA. SultanaA. KumarR. KhanY. GuptaG. Connecting the dots: LncRNAs in the KRAS pathway and cancer.Pathol. Res. Pract.202426215557010.1016/j.prp.2024.15557039226802
     [Google Scholar]
  136. DuX. VolkovO.A. CzerwinskiR.M. TanH. HuertaC. MortonE.R. RizziJ.P. WehnP.M. XuR. NijhawanD. WallaceE.M. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820.Structure2019271116251633.e310.1016/j.str.2019.10.00531693911
     [Google Scholar]
  137. UeharaT. MinoshimaY. SaganeK. SugiN.H. MitsuhashiK.O. YamamotoN. KamiyamaH. TakahashiK. KotakeY. UesugiM. YokoiA. InoueA. YoshidaT. MabuchiM. TanakaA. OwaT. Selective degradation of splicing factor CAPERα by anticancer sulfonamides.Nat. Chem. Biol.201713667568010.1038/nchembio.236328437394
     [Google Scholar]
  138. LiL. MiD. PeiH. DuanQ. WangX. ZhouW. JinJ. LiD. LiuM. ChenY. In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15.Signal Transduct. Target. Ther.20205112910.1038/s41392‑020‑00245‑032713946
     [Google Scholar]
  139. HussainM.S. GuptaG. MishraR. PatelN. GuptaS. AlzareaS.I. KazmiI. KumbharP. DisouzaJ. DurejaH. KukretiN. SinghS.K. DuaK. Unlocking the secrets: Volatile Organic Compounds (VOCs) and their devastating effects on lung cancer.Pathol. Res. Pract.202425515515710.1016/j.prp.2024.15515738320440
     [Google Scholar]
  140. WeiS. XingJ. ChenJ. ChenL. LvJ. ChenX. LiT. YuT. WangH. WangK. YuW. DCAF13 inhibits the p53 signaling pathway by promoting p53 ubiquitination modification in lung adenocarcinoma.J. Exp. Clin. Cancer Res.2024431310.1186/s13046‑023‑02936‑238163876
     [Google Scholar]
  141. GulatiN. ChellappanD.K. MacLoughlinR. GuptaG. SinghS.K. OliverB.G. DuaK. DurejaH. Advances in nano-based drug delivery systems for the management of cytokine influx-mediated inflammation in lung diseases.Naunyn Schmiedebergs Arch. Pharmacol.202439763695370710.1007/s00210‑023‑02882‑y38078921
     [Google Scholar]
  142. LiA.S.M. KimaniS. WilsonB. NoureldinM. González-ÁlvarezH. MamaiA. HofferL. GuilingerJ.P. ZhangY. von RechenbergM. DischJ.S. MulhernC.J. SlakmanB.L. CuozzoJ.W. DongA. PodaG. MohammedM. SaraonP. MittalM. ModhP. RathodV. PatelB. AcklooS. SanthakumarV. SzewczykM.M. Barsyte-LovejoyD. ArrowsmithC.H. MarcellusR. GuiéM.A. KeefeA.D. BrownP.J. HalabelianL. Al-awarR. VedadiM. Discovery of nanomolar DCAF1 small molecule ligands.J. Med. Chem.20236675041506010.1021/acs.jmedchem.2c0213236948210
     [Google Scholar]
  143. De RubisG. PaudelK.R. CorrieL. MehndirattaS. PatelV.K. KumbharP.S. ManjappaA.S. DisouzaJ. PatravaleV. GuptaG. ManandharB. RajputR. RobinsonA.K. ReyesR.J. ChakrabortyA. ChellappanD.K. SinghS.K. OliverB.G.G. HansbroP.M. DuaK. Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease.Naunyn Schmiedebergs Arch. Pharmacol.202439752793283310.1007/s00210‑023‑02830‑w37991539
     [Google Scholar]
  144. KimaniS.W. OwenJ. GreenS.R. LiF. LiY. DongA. BrownP.J. AcklooS. KuterD. YangC. MacAskillM. MacKinnonS.S. ArrowsmithC.H. SchapiraM. ShahaniV. HalabelianL. Discovery of a novel DCAF1 ligand using a drug–target interaction prediction model: Generalizing machine learning to new drug targets.J. Chem. Inf. Model.202363134070407810.1021/acs.jcim.3c0008237350740
     [Google Scholar]
  145. WangC. ZhangY. ChenW. WuY. XingD. New- generation advanced PROTACs as potential therapeutic agents in cancer therapy.Mol. Cancer202423111010.1186/s12943‑024‑02024‑938773495
     [Google Scholar]
  146. DahiyaR. SutariyaV.B. GuptaS.V. PantK. AliH. AlhadrawiM. KaurK. SharmaA. RajputP. GuptaG. AlmujriS.S. ChinniS.V. Harnessing pyroptosis for lung cancer therapy: The impact of NLRP3 inflammasome activation.Pathol. Res. Pract.202426015544410.1016/j.prp.2024.15544438986361
     [Google Scholar]
  147. ZoppiV. HughesS.J. ManiaciC. TestaA. GmaschitzT. WieshoferC. KoeglM. RichingK.M. DanielsD.L. SpallarossaA. CiulliA. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von hippel–lindau (VHL) based dual degrader probe of BRD9 and BRD7.J. Med. Chem.201962269972610.1021/acs.jmedchem.8b0141330540463
     [Google Scholar]
  148. BhatA.A. AfzalM. MogladE. ThapaR. AliH. AlmalkiW.H. KazmiI. AlzareaS.I. GuptaG. SubramaniyanV. lncRNAs as prognostic markers and therapeutic targets in cuproptosis-mediated cancer.Clin. Exp. Med.202424122610.1007/s10238‑024‑01491‑039325172
     [Google Scholar]
  149. LiangC. ShiX. FanC. Pathological and diagnostic implications of DCAF16 expression in human carcinomas including adenocarcinoma, squamous cell carcinoma, and urothelial carcinoma.Int. J. Clin. Exp. Pathol.20171088585859131966713
     [Google Scholar]
  150. DaviesT.G. WixtedW.E. CoyleJ.E. Griffiths-JonesC. HearnK. McMenaminR. NortonD. RichS.J. RichardsonC. SaxtyG. WillemsH.M.G. WoolfordA.J.A. CottomJ.E. KouJ.P. YonchukJ.G. FeldserH.G. SanchezY. FoleyJ.P. BologneseB.J. LoganG. PodolinP.L. YanH. CallahanJ.F. HeightmanT.D. KernsJ.K. Monoacidic inhibitors of the kelch-like ECH-associated protein 1: Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein–protein interaction with high cell potency identified by fragment-based discovery.J. Med. Chem.20165983991400610.1021/acs.jmedchem.6b0022827031670
     [Google Scholar]
  151. AraghiM. MannaniR. Heidarnejad malekiA. HamidiA. RostamiS. SafaS.H. FaramarziF. KhorasaniS. AlimohammadiM. TahmasebiS. Akhavan-SigariR. Recent advances in non-small cell lung cancer targeted therapy; An update review.Cancer Cell Int.202323116210.1186/s12935‑023‑02990‑y37568193
     [Google Scholar]
  152. YamamotoM. KenslerT.W. MotohashiH. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis.Physiol. Rev.20189831169120310.1152/physrev.00023.201729717933
     [Google Scholar]
  153. ManfordA.G. Rodríguez-PérezF. ShihK.Y. ShiZ. BerdanC.A. ChoeM. TitovD.V. NomuraD.K. RapeM. A cellular mechanism to detect and alleviate reductive stress.Cell202018314661.e2110.1016/j.cell.2020.08.03432941802
     [Google Scholar]
  154. HenningN.J. ManfordA.G. SpradlinJ.N. BrittainS.M. ZhangE. McKennaJ.M. TallaricoJ.A. SchirleM. RapeM. NomuraD.K. Discovery of a covalent FEM1B recruiter for targeted protein degradation applications.J. Am. Chem. Soc.2022144270170810.1021/jacs.1c0398034994556
     [Google Scholar]
  155. CordaniN. NovaD. SalaL. AbbateM.I. ColoneseF. CortinovisD.L. CanovaS. Proteolysis Targeting Chimera Agents (PROTACs): new hope for overcoming the resistance mechanisms in oncogene-addicted non-small cell lung cancer.Int. J. Mol. Sci.202425201121410.3390/ijms25201121439456995
     [Google Scholar]
  156. WardC.C. KleinmanJ.I. BrittainS.M. LeeP.S. ChungC.Y.S. KimK. PetriY. ThomasJ.R. TallaricoJ.A. McKennaJ.M. SchirleM. NomuraD.K. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications.ACS Chem. Biol.201914112430244010.1021/acschembio.8b0108331059647
     [Google Scholar]
  157. TongB. SpradlinJ.N. NovaesL.F.T. ZhangE. HuX. MoellerM. BrittainS.M. McGregorL.M. McKennaJ.M. TallaricoJ.A. SchirleM. MaimoneT.J. NomuraD.K. A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL.ACS Chem. Biol.20201571788179410.1021/acschembio.0c0034832568522
     [Google Scholar]
  158. LiX. PuW. ZhengQ. AiM. ChenS. PengY. Proteolysis-targeting chimeras (PROTACs) in cancer therapy.Mol. Cancer20222119910.1186/s12943‑021‑01434‑335410300
     [Google Scholar]
  159. WangC. ZhangY. WuY. XingD. Developments of CRBN-based PROTACs as potential therapeutic agents.Eur. J. Med. Chem.202122511374910.1016/j.ejmech.2021.11374934411892
     [Google Scholar]
  160. LiuY. OuyangL. MaoC. ChenY. LiuN. ChenL. ShiY. XiaoD. LiuS. TaoY. Inhibition of RNF182 mediated by Bap promotes non-small cell lung cancer progression.Front. Oncol.202312100950810.3389/fonc.2022.100950836686776
     [Google Scholar]
  161. FuX.Y. YinH. ChenX.T. YaoJ.F. MaY.N. SongM. XuH. YuQ.Y. DuS.S. QiY.K. WangK.W. Three rounds of stability-guided optimization and systematical evaluation of oncolytic peptide LTX-315.J. Med. Chem.20246753885390810.1021/acs.jmedchem.3c0223238278140
     [Google Scholar]
  162. GuanX. XuX. TaoY. DengX. HeL. LinZ. ChangJ. HuangJ. ZhouD. YuX. WeiM. ZhangL. Dual targeting and bioresponsive nano-PROTAC induced precise and effective lung cancer therapy.J. Nanobiotechnology202422169210.1186/s12951‑024‑02967‑739523308
     [Google Scholar]
  163. YinH. ChenX. ChiQ. MaY. FuX. DuS. QiY. WangK. The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus.Acta Pharmacol. Sin.202344120121010.1038/s41401‑022‑00939‑x35794372
     [Google Scholar]
  164. CaoZ. ZhuJ. WangZ. PengY. ZengL. Comprehensive pan-cancer analysis reveals ENC1 as a promising prognostic biomarker for tumor microenvironment and therapeutic responses.Sci. Rep.20241412533110.1038/s41598‑024‑76798‑939455818
     [Google Scholar]
  165. ZhouL. LuY. LiuW. WangS. WangL. ZhengP. ZiG. LiuH. LiuW. WeiS. Drug conjugates for the treatment of lung cancer: From drug discovery to clinical practice.Exp. Hematol. Oncol.20241312610.1186/s40164‑024‑00493‑838429828
     [Google Scholar]
  166. LiuH. TangY. ZhouQ. ZhangJ. LiX. GuH. HuB. LiY. The interrelation of blood urea nitrogen-to-albumin ratio with three-month clinical outcomes in acute ischemic stroke cases: A secondary analytical exploration derived from a prospective cohort study.Int. J. Gen. Med.2024175333534710.2147/IJGM.S48350539574467
     [Google Scholar]
  167. LouY. ZouX. PanZ. HuangZ. ZhengS. ZhengX. YangX. BaoM. ZhangY. GuJ. ZhangY. The mechanism of action of Botrychium (Thunb.) Sw. for prevention of idiopathic pulmonary fibrosis based on 1H-NMR-based metabolomics.J. Pharm. Pharmacol.20247681018102710.1093/jpp/rgae05838776436
     [Google Scholar]
  168. LinX. LiaoY. ChenX. LongD. YuT. ShenF. Regulation of oncoprotein 18/stathmin signaling by ERK concerns the resistance to taxol in nonsmall cell lung cancer cells.Cancer Biother. Radiopharm.2016312374310.1089/cbr.2015.192126881937
     [Google Scholar]
  169. ZhuangM. GuanS. WangH. BurlingameA.L. WellsJ.A. Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase, the NEDDylator.Mol. Cell201349227328210.1016/j.molcel.2012.10.02223201124
     [Google Scholar]
  170. NieY. LiD. PengY. WangS. HuS. LiuM. DingJ. ZhouW. Metal organic framework coated MnO2 nanosheets delivering doxorubicin and self-activated DNAzyme for chemo-gene combinatorial treatment of cancer.Int. J. Pharm.202058511951310.1016/j.ijpharm.2020.11951332526334
     [Google Scholar]
  171. SkaarJ.R. PaganJ.K. PaganoM. SCF ubiquitin ligase-targeted therapies.Nat. Rev. Drug Discov.2014131288990310.1038/nrd443225394868
     [Google Scholar]
  172. JiangC.H. SunT.L. XiangD.X. WeiS.S. LiW.Q. Anticancer activity and mechanism of xanthohumol: A prenylated flavonoid from hops (Humulus lupulus L.).Front. Pharmacol.2018953010.3389/fphar.2018.0053029872398
     [Google Scholar]
  173. BuetowL. HuangD.T. Structural insights into the catalysis and regulation of E3 ubiquitin ligases.Nat. Rev. Mol. Cell Biol.2016171062664210.1038/nrm.2016.9127485899
     [Google Scholar]
  174. JiangY. ChenR. XuS. DingY. ZhangM. BaoM. HeB. LiS. Endocrine and metabolic factors and the risk of idiopathic pulmonary fibrosis: A Mendelian randomization study.Front. Endocrinol. (Lausanne)202414132157610.3389/fendo.2023.132157638260151
     [Google Scholar]
  175. LiY. WangN. HuangY. HeS. BaoM. WenC. WuL. CircMYBL1 suppressed acquired resistance to osimertinib in non-small-cell lung cancer.Cancer Genet.2024284-285344210.1016/j.cancergen.2024.04.00138626533
     [Google Scholar]
  176. ZhaoC. SongW. WangJ. TangX. JiangZ. Immunoadjuvant-functionalized metal–organic frameworks: Synthesis and applications in tumor immune modulation.Chem. Commun. (Camb.)202561101962197710.1039/D4CC06510G39774558
     [Google Scholar]
  177. OttP.A. HodiF.S. RobertC. CTLA-4 and PD-1/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients.Clin. Cancer Res.201319195300530910.1158/1078‑0432.CCR‑13‑014324089443
     [Google Scholar]
  178. DongQ. JiangZ. Platinum–iron nanoparticles for oxygen-enhanced sonodynamic tumor cell suppression.Inorganics (Basel)2024121233110.3390/inorganics12120331
     [Google Scholar]
  179. FongP.C. BossD.S. YapT.A. TuttA. WuP. Mergui-RoelvinkM. MortimerP. SwaislandH. LauA. O’ConnorM.J. AshworthA. CarmichaelJ. KayeS.B. SchellensJ.H.M. de BonoJ.S. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N. Engl. J. Med.2009361212313410.1056/NEJMoa090021219553641
     [Google Scholar]
  180. HussainM.S. SharmaS. KumariA. KamranA. BahlG. BishtA.S. SultanaA. AshiqueS. RamalingamP.S. ArumugamS. Role of long non-coding RNAs in neurofibromatosis and Schwannomatosis: Pathogenesis and therapeutic potential.Epigenomics20241623-241453146410.1080/17501911.2024.243017039601046
     [Google Scholar]
  181. YinD. ZhongY. LingS. LuS. WangX. JiangZ. WangJ. DaiY. TianX. HuangQ. WangX. ChenJ. LiZ. LiY. XuZ. JiangH. WuY. ShiY. WangQ. XuJ. HongW. XueH. YangH. ZhangY. DaL. HanZ. TaoS. DongR. YingT. HongJ. CaiY. Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers.Nat. Biomed. Eng.20249218520010.1038/s41551‑024‑01208‑438714892
     [Google Scholar]
  182. HanzlA. WinterG.E. Targeted protein degradation: Current and future challenges.Curr. Opin. Chem. Biol.202056354110.1016/j.cbpa.2019.11.01231901786
     [Google Scholar]
  183. LiZ. FanJ. XiaoY. WangW. ZhenC. PanJ. WuW. LiuY. ChenZ. YanQ. ZengH. LuoS. LiuL. TuZ. ZhaoX. HouY. Essential role of Dhx16-mediated ribosome assembly in maintenance of hematopoietic stem cells.Leukemia202438122699270810.1038/s41375‑024‑02423‑339333759
     [Google Scholar]
  184. BanikS.M. PedramK. WisnovskyS. AhnG. RileyN.M. BertozziC.R. Lysosome-targeting chimaeras for degradation of extracellular proteins.Nature2020584782029129710.1038/s41586‑020‑2545‑932728216
     [Google Scholar]
  185. TakahashiD. MoriyamaJ. NakamuraT. MikiE. TakahashiE. SatoA. AkaikeT. Itto-NakamaK. ArimotoH. AUTACs: Cargo-specific degraders using selective autophagy.Mol. Cell2019765797810.e1010.1016/j.molcel.2019.09.00931606272
     [Google Scholar]
  186. YangZ. LiuX. XuH. TeschendorffA.E. XuL. LiJ. FuM. LiuJ. ZhouH. WangY. ZhangL. HeY. LvK. YangH. Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma.Commun. Biol.20247182410.1038/s42003‑024‑06488‑938971948
     [Google Scholar]
  187. LiZ. XiaoC. YongT. LiZ. GanL. YangX. Influence of nanomedicine mechanical properties on tumor targeting delivery.Chem. Soc. Rev.20204982273229010.1039/C9CS00575G32215407
     [Google Scholar]
  188. YangH. LiQ. ChenX. WengM. HuangY. ChenQ. LiuX. HuangH. FengY. ZhouH. ZhangM. PeiW. LiX. FuQ. ZhuL. WangY. KongX. LvK. ZhangY. SunY. MaM. Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer.Nat. Commun.2024151429610.1038/s41467‑024‑48307‑z38769295
     [Google Scholar]
  189. GaoJ. HouB. ZhuQ. YangL. JiangX. ZouZ. LiX. XuT. ZhengM. ChenY.H. XuZ. XuH. YuH. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy.Nat. Commun.2022131431810.1038/s41467‑022‑32050‑435882867
     [Google Scholar]
  190. GaoY. DuanJ. DangX. YuanY. WangY. HeX. BaiR. YeX.Y. XieT. Design, synthesis and biological evaluation of novel histone deacetylase (HDAC) inhibitors derived from β-elemene scaffold.J. Enzyme Inhib. Med. Chem.2023381219599110.1080/14756366.2023.219599137013860
     [Google Scholar]
  191. WuD. YangK. ZhangZ. FengY. RaoL. ChenX. YuG. Metal-free bioorthogonal click chemistry in cancer theranostics.Chem. Soc. Rev.20225141336137610.1039/D1CS00451D35050284
     [Google Scholar]
  192. ZhangC. ZengZ. CuiD. HeS. JiangY. LiJ. HuangJ. PuK. Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy.Nat. Commun.2021121293410.1038/s41467‑021‑23194‑w34006860
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673382742250619055201
Loading
Targeted Protein Degradation in Lung Cancer: The Emerging Role of PROTAC Technology and E3 Ligases
Curr. Med. Chem. 33, 1151 (2026); https://doi.org/10.2174/0109298673382742250619055201
/content/journals/cmc/10.2174/0109298673382742250619055201
/content/journals/cmc/10.2174/0109298673382742250619055201
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): E3 ligases; EGFR; fusion proteins; Lung cancer; PROTACs; Ubiquitin-proteasome system

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test