Skip to content
2000
Volume 21, Issue 4
  • ISSN: 1573-3947
  • E-ISSN: 1875-6301

Abstract

Targeted protein degradation is a rapidly expanding area that offers hope for novel approaches to combat drug resistance. The creation of heterobifunctional proteolysis-targeting chimeras [PROTACs], a new group of pharmaceutical compounds, has made TPD a useful method for completely getting rid of harmful proteins using regular small-molecule inhibitors. A big plus is that PROTACs can target multi-domain proteins that cannot be broken down. This is the case, particularly for proteins lacking a conserved interaction surface for small-molecule ligands SMIs and featuring smooth surfaces. Poor oral bioavailability and pharmacokinetic PK and ADMET absorption, distribution, metabolism, excretion, and toxicity characteristics are among the long-term issues with traditional PROTACs. Their larger size and more complex structure set them apart from other small-molecule inhibitors, which is why they are so effective. Clinical studies have been conducted on a plethora of PROTAC compounds in the past 20 years, all with the goal of inducing the degradation of targets relevant to cancer. In this article, we closely examine the major developments and recent advancements in PROTAC technology. We seek to summarize and fully assess PROTAC-based targeted protein degradation studies on “undruggable” targets. Discussing their molecular structure, action mechanism, design concepts, development benefits, and obstacles will help to illustrate the significance of developing highly successful PROTAC-based techniques in treating many illnesses, including cancer treatment resistance.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cctr/10.2174/0115733947304955240430124514
2024-05-14
2025-09-02

  • From This Site

    /content/journals/cctr/10.2174/0115733947304955240430124514
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. GharwanH. GroningerH. Kinase inhibitors and monoclonal antibodies in oncology: Clinical implications.Nat. Rev. Clin. Oncol.201613420922710.1038/nrclinonc.2015.213 26718105
     [Google Scholar]
  2. WangC. ZhengC. WangH. ZhangL. LiuZ. XuP. The state of the art of PROTAC technologies for drug discovery.Eur. J. Med. Chem.202223511429010.1016/j.ejmech.2022.114290 35307618
     [Google Scholar]
  3. LiD. YuD. LiY. YangR. A bibliometric analysis of PROTAC from 2001 to 2021.Eur. J. Med. Chem.202224411483810.1016/j.ejmech.2022.114838 36274273
     [Google Scholar]
  4. WangR. SongS. QinJ. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.Cancer Cell202341814071426.e910.1016/j.ccell.2023.06.005 37419119
     [Google Scholar]
  5. BurkeM.R. SmithA.R. ZhengG. Overcoming cancer drug resistance utilizing protac technology.Front. Cell Dev. Biol.20221087272910.3389/fcell.2022.872729 35547806
     [Google Scholar]
  6. FarcO. CristeaV. An overview of the tumor microenvironment, from cells to complex networks.Exp. Ther. Med.20202119610.3892/etm.2020.9528 33363607
     [Google Scholar]
  7. De GuillebonE. DardenneA. SaldmannA. Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination.Int. J. Cancer202014761509151810.1002/ijc.32889 31997345
     [Google Scholar]
  8. BożykA. Wojas-KrawczykK. KrawczykP. MilanowskiJ. Tumor microenvironment-a short review of cellular and interaction diversity.Biology202211692910.3390/biology11060929
     [Google Scholar]
  9. BarghoutS.H. New frontiers in the discovery and development of PROTACs.Anticancer. Agents Med. Chem.202222152656266110.2174/1871520622666220412132759 35418290
     [Google Scholar]
  10. TamatamR. ShinD. Emerging strategies in proteolysis-targeting chimeras (PROTACs): Highlights from 2022.Int. J. Mol. Sci.2023246519010.3390/ijms24065190
     [Google Scholar]
  11. Irshad KhanM.Z. NazliA. PanY.L. ChenJ.Z. Recent developments in medicinal chemistry and therapeutic potential of anti-cancer PROTACs-based molecules.Curr. Med. Chem.202330141576162210.2174/0929867329666220803112409 35927805
     [Google Scholar]
  12. KhanS. HeY. ZhangX. PROteolysis targeting chimeras (PROTACs) as emerging anticancer therapeutics.Oncogene202039264909492410.1038/s41388‑020‑1336‑y 32475992
     [Google Scholar]
  13. GaoJ. HouB. ZhuQ. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy.Nat. Commun.2022131431810.1038/s41467‑022‑32050‑4 35882867
     [Google Scholar]
  14. HiraiK. YamashitaH. TomoshigeS. Conversion of a PROTAC mutant huntingtin degrader into small-molecule hydrophobic tags focusing on drug-like properties.ACS Med. Chem. Lett.202213339640210.1021/acsmedchemlett.1c00500 35300080
     [Google Scholar]
  15. MaresA. MiahA.H. SmithI.E.D. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.Commun. Biol.20203114010.1038/s42003‑020‑0868‑6 32198438
     [Google Scholar]
  16. LiuJ. PengY. InuzukaH. WeiW. Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.Semin. Cancer Biol.202286Pt 226927910.1016/j.semcancer.2022.07.001 35798235
     [Google Scholar]
  17. PatelS. PatelN. How to Use QbD to Select Packaging Components.2017Available from: https://www.pda.org/pda-letter-portal/home/full-article/how-to-use-qbd-to-select-packaging-components
    [Google Scholar]
  18. PikeA. WilliamsonB. HarlfingerS. MartinS. McGinnityD.F. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: A drug metabolism and pharmacokinetics perspective.Drug Discov. Today202025101793180010.1016/j.drudis.2020.07.013 32693163
     [Google Scholar]
  19. TashimaT. Proteolysis-targeting chimera (PROTAC) delivery into the brain across the blood-brain barrier.Antibodies20231234310.3390/antib12030043
     [Google Scholar]
  20. LiJ.W. ZhengG. KayeF.J. WuL. PROTAC therapy as a new targeted therapy for lung cancer.Mol. Ther.202331364765610.1016/j.ymthe.2022.11.011 36415148
     [Google Scholar]
  21. ChenY. YangQ. XuJ. PROTACs in gastrointestinal cancers.Mol. Ther. Oncolytics20222720422310.1016/j.omto.2022.10.012 36420306
     [Google Scholar]
  22. ZhaoC. DekkerF.J. Novel design strategies to enhance the efficiency of proteolysis targeting chimeras.ACS Pharmacol. Transl. Sci.20225971072310.1021/acsptsci.2c00089 36110375
     [Google Scholar]
  23. TunjicT.M. WeberN. BrunsteinerM. Computer aided drug design in the development of proteolysis targeting chimeras.Comput. Struct. Biotechnol. J.2023212058206710.1016/j.csbj.2023.02.042 36968015
     [Google Scholar]
  24. MoonY. JeonS.I. ShimM.K. KimK. Cancer-specific delivery of proteolysis-targeting chimeras (PROTACs) and their application to cancer immunotherapy.Pharmaceutics202315241110.3390/pharmaceutics15020411 36839734
     [Google Scholar]
  25. KelmJ.M. PandeyD.S. MalinE. PROTAC’ing oncoproteins: Targeted protein degradation for cancer therapy.Mol. Cancer20232216210.1186/s12943‑022‑01707‑5 36991452
     [Google Scholar]
  26. NeklesaT.K. WinklerJ.D. CrewsC.M. Targeted protein degradation by PROTACs.Pharmacol. Ther.201717413814410.1016/j.pharmthera.2017.02.027 28223226
     [Google Scholar]
  27. ZengS. HuangW. ZhengX. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges.Eur. J. Med. Chem.202121011298110.1016/j.ejmech.2020.112981 33160761
     [Google Scholar]
  28. LvM. HuW. ZhangS. HeL. HuC. YangS. Proteolysis-targeting chimeras: A promising technique in cancer therapy for gaining insights into tumor development.Cancer Lett.202253921571610.1016/j.canlet.2022.215716 35500825
     [Google Scholar]
  29. JinJ. WuY. ChenJ. The peptide PROTAC modality: A novel strategy for targeted protein ubiquitination.Theranostics20201022101411015310.7150/thno.46985 32929339
     [Google Scholar]
  30. ToureM. CrewsC.M. Small‐molecule PROTACs: New approaches to protein degradation.Angew. Chem. Int. Ed.20165561966197310.1002/anie.201507978 26756721
     [Google Scholar]
  31. PaivaS.L. CrewsC.M. Targeted protein degradation: Elements of PROTAC design.Curr. Opin. Chem. Biol.20195011111910.1016/j.cbpa.2019.02.022 31004963
     [Google Scholar]
  32. BékésM. LangleyD.R. CrewsC.M. PROTAC targeted protein degraders: The past is prologue.Nat. Rev. Drug Discov.202221318120010.1038/s41573‑021‑00371‑6 35042991
     [Google Scholar]
  33. OhokaN. ShibataN. HattoriT. NaitoM. Protein knockdown technology: Application of ubiquitin ligase to cancer therapy.Curr. Cancer Drug Targets201616213614610.2174/1568009616666151112122502 26560118
     [Google Scholar]
  34. DuffyM.J. SynnottN.C. McGowanP.M. CrownJ. O’ConnorD. GallagherW.M. p53 as a target for the treatment of cancer.Cancer Treat. Rev.201440101153116010.1016/j.ctrv.2014.10.004 25455730
     [Google Scholar]
  35. 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‑18‑2918 30385614
     [Google Scholar]
  36. DaleB. ChengM. ParkK.S. KaniskanH.Ü. XiongY. JinJ. Advancing targeted protein degradation for cancer therapy.Nat. Rev. Cancer2021211063865410.1038/s41568‑021‑00365‑x 34131295
     [Google Scholar]
  37. LiX. SongY. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy.J. Hematol. Oncol.20201315010.1186/s13045‑020‑00885‑3 32404196
     [Google Scholar]
  38. BuckleyD.L. GustafsonJ.L. Van MolleI. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α.Angew. Chem. Int. Ed.20125146114631146710.1002/anie.201206231 23065727
     [Google Scholar]
  39. BuckleyD.L. Van MolleI. GareissP.C. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction.J. Am. Chem. Soc.2012134104465446810.1021/ja209924v 22369643
     [Google Scholar]
  40. ZengerleM. ChanK.H. CiulliA. Selective small molecule induced degradation of the BET bromodomain protein BRD4.ACS Chem. Biol.20151081770177710.1021/acschembio.5b00216 26035625
     [Google Scholar]
  41. RainaK. LuJ. QianY. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.Proc. Natl. Acad. Sci. USA2016113267124712910.1073/pnas.1521738113 27274052
     [Google Scholar]
  42. SaenzD.T. FiskusW. QianY. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.Leukemia20173191951196110.1038/leu.2016.393 28042144
     [Google Scholar]
  43. GaddM.S. TestaA. LucasX. Structural basis of PROTAC cooperative recognition for selective protein degradation.Nat. Chem. Biol.201713551452110.1038/nchembio.2329 28288108
     [Google Scholar]
  44. BraunT.P. EideC.A. DrukerB.J. Response and resistance to BCR-ABL1-targeted therapies.Cancer Cell202037453054210.1016/j.ccell.2020.03.006 32289275
     [Google Scholar]
  45. GuptaP. ZhangG.N. BarbutiA.M. Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia.Cancer Lett.202047213214110.1016/j.canlet.2019.11.040 31837444
     [Google Scholar]
  46. ZhaoQ. RenC. LiuL. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting von hippel–lindau (VHL) E3 ubiquitin ligase.J. Med. Chem.201962209281929810.1021/acs.jmedchem.9b01264 31539241
     [Google Scholar]
  47. ItoT. AndoH. SuzukiT. Identification of a primary target of thalidomide teratogenicity.Science201032759711345135010.1126/science.1177319 20223979
     [Google Scholar]
  48. LuJ. QianY. AltieriM. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4.Chem. Biol.201522675576310.1016/j.chembiol.2015.05.009 26051217
     [Google Scholar]
  49. WinterG.E. BuckleyD.L. PaulkJ. RobertsJ.M. SouzaA. Dhe-PaganonS. Phthalimide conjugation as a strategy for in vivo target protein degradation.Science201534862411376138110.1126/science.aab1433
     [Google Scholar]
  50. QinC. HuY. ZhouB. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression.J. Med. Chem.201861156685670410.1021/acs.jmedchem.8b00506 30019901
     [Google Scholar]
  51. ZhangH. LiG. ZhangY. Targeting BET proteins with a PROTAC molecule elicits potent anticancer activity in HCC cells.Front. Oncol.20209147110.3389/fonc.2019.01471 31993368
     [Google Scholar]
  52. BurgerJ.A. WiestnerA. Targeting B cell receptor signalling in cancer: Preclinical and clinical advances.Nat. Rev. Cancer201818314816710.1038/nrc.2017.121 29348577
     [Google Scholar]
  53. WoyachJ.A. RuppertA.S. GuinnD. BTKC481S -mediated resistance to ibrutinib in chronic lymphocytic leukemia.J. Clin. Oncol.201735131437144310.1200/JCO.2016.70.2282 28418267
     [Google Scholar]
  54. SunY. DingN. SongY. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas.Leukemia20193382105211010.1038/s41375‑019‑0440‑x 30858551
     [Google Scholar]
  55. HallbergB. PalmerR.H. The role of the ALK receptor in cancer biology.Ann. Oncol.201627Suppl. 3iii4iii1510.1093/annonc/mdw301 27573755
     [Google Scholar]
  56. SodaM. ChoiY.L. EnomotoM. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer.Nature2007448715356156610.1038/nature05945 17625570
     [Google Scholar]
  57. KangC.H. LeeD.H. LeeC.O. Du HaJ. ParkC.H. HwangJ.Y. Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC).Biochem. Biophys. Res. Commun.2018505254254710.1016/j.bbrc.2018.09.169 30274779
     [Google Scholar]
  58. FinnR.S. MartinM. RugoH.S. Palbociclib and letrozole in advanced breast cancer.N. Engl. J. Med.2016375201925193610.1056/NEJMoa1607303 27959613
     [Google Scholar]
  59. SuS. YangZ. GaoH. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders.J. Med. Chem.201962167575758210.1021/acs.jmedchem.9b00871 31330105
     [Google Scholar]
  60. WangZ. HeN. GuoZ. Proteolysis targeting chimeras for the selective degradation of Mcl-1/Bcl-2 derived from nonselective target binding ligands.J. Med. Chem.201962178152816310.1021/acs.jmedchem.9b00919 31389699
     [Google Scholar]
  61. PapatzimasJ.W. GorobetsE. MaityR. From inhibition to degradation: Targeting the antiapoptotic protein myeloid cell leukemia 1 (MCL1).J. Med. Chem.201962115522554010.1021/acs.jmedchem.9b00455 31117518
     [Google Scholar]
  62. FelthamR. BettjemanB. BudhidarmoR. Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization.J. Biol. Chem.201128619170151702810.1074/jbc.M111.222919 21393245
     [Google Scholar]
  63. JinY.H. LuM.C. WangY. Azo-PROTAC: Novel light-controlled small-molecule tool for protein knockdown.J. Med. Chem.20206394644465410.1021/acs.jmedchem.9b02058 32153174
     [Google Scholar]
  64. PfaffP. SamarasingheK.T.G. CrewsC.M. CarreiraE.M. Reversible spatiotemporal control of induced protein degradation by bistable photoPROTACs.ACS Cent. Sci.20195101682169010.1021/acscentsci.9b00713 31660436
     [Google Scholar]
  65. ReyndersM. MatsuuraB.S. BéroutiM. PHOTACs enable optical control of protein degradation.Sci. Adv.202068eaay506410.1126/sciadv.aay5064 32128406
     [Google Scholar]
  66. NaroY. DarrahK. DeitersA. Optical control of small molecule-induced protein degradation.J. Am. Chem. Soc.202014252193219710.1021/jacs.9b12718 31927988
     [Google Scholar]
  67. XueG. WangK. ZhouD. ZhongH. PanZ. Light-induced protein degradation with photocaged PROTACs.J. Am. Chem. Soc.201914146183701837410.1021/jacs.9b06422 31566962
     [Google Scholar]
  68. LebraudH. WrightD.J. JohnsonC.N. HeightmanT.D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras.ACS Cent. Sci.201621292793410.1021/acscentsci.6b00280 28058282
     [Google Scholar]
  69. CecchiniC. PannilunghiS. TardyS. ScapozzaL. From conception to development: Investigating PROTACs features for improved cell permeability and successful protein degradation.Front Chem.2021967226710.3389/fchem.2021.672267 33959589
     [Google Scholar]
  70. BuckleyD.L. RainaK. DarricarrereN. HaloPROTACs: Use of small molecule PROTACs to induce degradation of halotag fusion proteins.ACS Chem. Biol.20151081831183710.1021/acschembio.5b00442 26070106
     [Google Scholar]
  71. TomoshigeS. NaitoM. HashimotoY. IshikawaM. Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules.Org. Biomol. Chem.201513389746975010.1039/C5OB01395J 26338696
     [Google Scholar]
  72. ZhaoL. ZhaoJ. ZhongK. TongA. JiaD. Targeted protein degradation: Mechanisms, strategies and application.Signal Transduct. Target. Ther.20227111310.1038/s41392‑022‑00966‑4 35379777
     [Google Scholar]
  73. 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.2021.692574 34025443
     [Google Scholar]
  74. SincereN.I. AnandK. AshiqueS. YangJ. YouC. PROTACs: Emerging targeted protein degradation approaches for advanced druggable strategies.Molecules20232810401410.3390/molecules28104014 37241755
     [Google Scholar]
  75. ZhongY. ChiF. WuH. Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond.Eur. J. Med. Chem.202223111414210.1016/j.ejmech.2022.114142 35092900
     [Google Scholar]
  76. NalawanshaD.A. CrewsC.M. PROTACs: An emerging therapeutic modality in precision medicine.Cell Chem. Biol.2020278998101410.1016/j.chembiol.2020.07.020 32795419
     [Google Scholar]
  77. LiR. LiuM. YangZ. LiJ. GaoY. TanR. Proteolysis-targeting chimeras (PROTACs) in cancer therapy: Present and future.Molecules20222724882810.3390/molecules27248828 36557960
     [Google Scholar]
/content/journals/cctr/10.2174/0115733947304955240430124514
Loading
Anticancer Therapy with Proteolysis-targeting Chimeras [PROTACs] Targeting the Tumor-microenvironment: Development, Current State and Prospects
Curr Cancer Ther Rev 21, 443 (2025); https://doi.org/10.2174/0115733947304955240430124514
/content/journals/cctr/10.2174/0115733947304955240430124514
/content/journals/cctr/10.2174/0115733947304955240430124514
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): ADMET absorption; and toxicity; distribution; excretion; metabolism; pharmacokinetics; Proteolysis-Targeting chimeras; small-molecule inhibitors; targeted protein degradation; targeting cancer therapy

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