Keywords
Ubiquitin-proteasome system
Targeted therapy
Next-generation PROTAC
Submitted : 2026-01-10
Accepted : 2026-01-25
Published : 2026-02-09
Abstract
In recent years, proteolysis-targeting chimeras (PROTACs) have gained widespread attention as an emerging therapeutic approach. PROTACs are bifunctional molecules composed of a target protein-binding ligand, an E3 ubiquitin ligase ligand, and a linker connecting these ligands. By harnessing the cell’s intrinsic ubiquitin-proteasome system (UPS), they promote the ubiquitination of specific target proteins, leading to their degradation and therapeutic effects. PROTACs show exceptional promise in targeting conventional “undruggable” targets compared to traditional small-molecule inhibitors. This review provides an overview of PROTACs, including their molecular mechanism of action, therapeutic benefits, development history, key design aspects, current research and development challenges, and future trends in next-generation PROTAC technology.
References
Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer Journal for Clinicians, 74(3): 229–263.
Zhong L, Li Y, Xiong L, et al., 2021, Small Molecules in Targeted Cancer Therapy: Advances, Challenges, and Future Perspectives. Signal Transduction and Targeted Therapy, 6(1): 201.
Békés M, Langley D R, Crews C M, 2022, PROTAC Targeted Protein Degraders: The Past Is Prologue. Nature Reviews Drug Discovery, 21(3): 181–200.
Carreira L, Oliveira R, Moreira V, et al., 2023, Ubiquitin-Specific Protease 7 (USP7): An Emerging Drug Target for Cancer Treatment. Expert Opinion on Therapeutic Targets, 27(11): 1043–1058.
Qi S, Dong J, Xu Z, et al., 2021, PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Frontiers in Pharmacology, 12: 692574.
Dang C, Reddy E, Shokat K, et al., 2017, Drugging the “Undruggable” Cancer Targets. Nature Reviews Cancer, 17(8): 502–508.
Gourisankar S, Krokhotin A, Ji W, et al., 2023, Rewiring Cancer Drivers to Activate Apoptosis. Nature, 620(7973): 417–425.
Sun Q, Cai D, Liu D, et al., 2023, BCL6 Promotes a Stem-Like CD8+ T Cell Program in Cancer via Antagonizing BLIMP1. Science Immunology, 8(88): eadh1306.
Liongue C, Almohaisen F, Ward A, 2024, B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. International Journal of Molecular Sciences, 25(20): 10968.
Mascle X, Albagli O, Lemercier C, 2003, Point Mutations in BCL6 DNA-Binding Domain Reveal Distinct Roles for the Six Zinc Fingers. Biochemical and Biophysical Research Communications, 300(2): 391–396.
Groocock L, Deb G, Zhu J, et al., 2024, BMS-986458, a Potential First-in-Class, Highly Selective, Potent and Well Tolerated BCL6 Ligand Directed Degrader (LDD) Demonstrates Multi-Modal Anti-Tumor Efficacy for the Treatment of B-Cell Non-Hodgkin’s Lymphoma. Blood, 144: 957.
Raina K, Lu J, Qian Y, et al., 2016, PROTAC-Induced BET Protein Degradation as a Therapy for Castration-Resistant Prostate Cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(26): 7124–7129.
Gough S, Sherman D, DeCarr L, et al., 2021, Potent and Orally Bioavailable BCL6 PROTAC TM Degraders Demonstrate Efficacy in Pre-Clinical Models of Diffuse Large B-Cell Lymphoma (DLBCL). Blood, 138: 2272.
Sherman D, 2024, Abstract ND05: The Discovery of ARV-393, a Potent, Orally Bioavailable BCL6 Targeting PROTAC® for the Treatment of Non-Hodgkin’s Lymphoma. Cancer Research, 84: ND05.
Roskoski R, 2020, Properties of FDA-Approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacological Research, 152: 104609.
Sun X, Rao Y, 2019, PROTACs as Potential Therapeutic Agents for Cancer Drug Resistance. Biochemistry, 59(3): 240–249.
Peng L, Zhu L, Sun Y, et al., 2022, Targeting ALK Rearrangements in NSCLC: Current State of the Art. Frontiers in Oncology, 12: 863461.
Yoda S, Lin J, Lawrence M, et al., 2018, Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discovery, 8(6): 714–729.
Dagogo-Jack I, Rooney M, Lin J, et al., 2019, Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity. Clinical Cancer Research, 25(22): 6662–6670.
Gao F, Wu Z, Lin A, et al., 2025, Discovery of an ALK Degrader for Lorlatinib-Resistant Compound Mutations. European Journal of Medicinal Chemistry: 117835.
Churcher I, 2018, PROTAC-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? Bioorganic Chemistry, 61(2): 444–452.
Li Y, Zhang C, Martincuks A, et al., 2023, STAT Proteins in Cancer: Orchestration of Metabolism. Nature Reviews Cancer, 23(3): 115–134.
Li S, Wang X, Huang J, et al., 2025, Decoy-PROTAC for Specific Degradation of “Undruggable” STAT3 Transcription Factor. Cell Death & Disease, 16(1): 197.
Sakamoto K, Kim K, Kumagai A, et al., 2001, Protacs: Chimeric Molecules That Target Proteins to the Skp1–Cullin–F Box Complex for Ubiquitination and Degradation. Proceedings of the National Academy of Sciences of the United States of America, 98(15): 8554–8559.
Schneekloth A, Pucheault M, Tae H, et al., 2008, Targeted Intracellular Protein Degradation Induced by a Small Molecule: En Route to Chemical Proteomics. Bioorganic & Medicinal Chemistry Letters, 18(22): 5904–5908.
Itoh Y, Ishikawa M, Naito M, et al., 2010, Protein Knockdown Using Methyl Bestatin-Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins. Journal of the American Chemical Society, 132(16): 5820–5826.
Bondeson D, Mares A, Smith I, et al., 2015, Catalytic In Vivo Protein Knockdown by Small-Molecule PROTACs. Nature Chemical Biology, 11(8): 611–617.
Winter G, Buckley D, Paulk J, et al., 2015, Phthalimide Conjugation as a Strategy for In Vivo Target Protein Degradation. Science, 348(6241): 1376–1381.
Neklesa T, Snyder L, Willard R, et al., 2019, ARV-110: An Oral Androgen Receptor PROTAC Degrader for Prostate Cancer. Journal of Clinical Oncology, 37(259): 10.1200.
Mullard A, 2019, Arvinas’s PROTACs Pass First Safety and PK Analysis. Nature Reviews Drug Discovery, 18(12): 895–896.
Ge R, Chen M, Li Q, et al., 2025, Targeting Neurodegenerative Disease-Associated Protein Aggregation with Proximity-Inducing Modalities. Acta Pharmacologica Sinica: 1–10.
Huang X, Wu F, Ye J, et al., 2024, Expanding the Horizons of Targeted Protein Degradation: A Non-Small Molecule Perspective. Acta Pharmaceutica Sinica B, 14(6): 2402–2427.
Yang N, Kong B, Zhu Z, et al., 2024, Recent Advances in Targeted Protein Degraders as Potential Therapeutic Agents. Molecular Diversity, 28(1): 309–333.
Zhou C, Fan Z, Gu Y, et al., 2024, Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D. Journal of Medicinal Chemistry, 67(2): 1147–1167.
Jiang H, Xiong H, Gu S, et al., 2023, E3 Ligase Ligand Optimization of Clinical PROTACs. Frontiers in Chemistry, 11: 1098331.
Sobierajski T, Małolepsza J, Pichlak M, et al., 2024, The Impact of E3 Ligase Choice on PROTAC Effectiveness in Protein Kinase Degradation. Drug Discovery Today, 29(7): 104032.
Lee J, Lee Y, Jung Y M, et al., 2022, Discovery of E3 Ligase Ligands for Target Protein Degradation. Molecules, 27(19): 6515.
Thomas B, Lewis H, Jones D, et al., 2023, Central Nervous System Targeted Protein Degraders. Biomolecules, 13(8): 1164.
Bemis T, La Clair J, Burkart M, 2021, Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras: Miniperspective. Journal of Medicinal Chemistry, 64(12): 8042–8052.
Zografou-Barredo N, Hallatt A, Goujon-Ricci J, et al., 2023, A Beginner’s Guide to Current Synthetic Linker Strategies towards VHL-Recruiting PROTACs. Bioorganic & Medicinal Chemistry, 88: 117334.
Li S, Zeng T, Wu Z, et al., 2025, DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting. European Journal of Medicinal Chemistry, 147(2): 2168–2181.
Zhang J, Chen C, Chen X, et al., 2025, Linker-Free PROTACs Efficiently Induce the Degradation of Oncoproteins. Nature Communications, 16(1): 4794.
Drummond M, Henry A, Li H, et al., 2020, Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In Silico Methodologies. Journal of Chemical Information and Modeling, 60(10): 5234–5254.
Maniaci C, Ciulli A, 2019, Bifunctional Chemical Probes Inducing Protein–Protein Interactions. Current Opinion in Chemical Biology, 52: 145–156.
Li W, Zhang J, Guo L, et al., 2022, Importance of Three-Body Problems and Protein–Protein Interactions in Proteolysis-Targeting Chimera Modeling: Insights from Molecular Dynamics Simulations. Journal of Chemical Information and Modeling, 62(3): 523–532.
Sternicki L, Nonomiya J, Liu M, et al., 2021, Native Mass Spectrometry for the Study of PROTAC GNE-987-Containing Ternary Complexes. ChemMedChem, 16(14): 2206–2210.
Ge J, Hsieh C Y, Fang M, et al., 2024, Development of PROTACs Using Computational Approaches. Trends in Pharmacological Sciences, 45(12): 1162–1174.
Mslati H, Gentile F, Pandey M, et al., 2024, PROTACable Is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning to Automate the De Novo Design of PROTACs. Journal of Chemical Information and Modeling, 64(8): 3034–3046.
Vicente A, Moura S, Salvador J, 2025, Synthesis, Biological Evaluation and Clinical Trials of Cereblon-Based PROTACs. Communications Chemistry, 8(1): 218.
Zeng S, Ye Y, Xia H, et al., 2023, Current Advances and Development Strategies of Orally Bioavailable PROTACs. European Journal of Medicinal Chemistry, 261: 115793.
Volak L, Duevel H, Humphreys S, et al., 2023, Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders. Drug Metabolism and Disposition, 51(7): 792–803.
Edmondson S, Yang B, Fallan C, 2019, Proteolysis Targeting Chimeras (PROTACs) in ‘Beyond Rule-of-Five’ Chemical Space: Recent Progress and Future Challenges. Bioorganic & Medicinal Chemistry Letters, 29(13): 1555–1564.
Ge R, Chen M, Wu S, et al., 2025, DNA Nanoflower Oligo-PROTAC for Targeted Degradation of FUS to Treat Neurodegenerative Diseases. Nature Communications, 16(1): 4683.
Zeng S, Huang W, Zheng X, et al., 2021, Proteolysis Targeting Chimera (PROTAC) in Drug Discovery Paradigm: Recent Progress and Future Challenges. European Journal of Medicinal Chemistry, 210: 112981.
Wang C, Zhang Y, Chen W, et al., 2024, New-Generation Advanced PROTACs as Potential Therapeutic Agents in Cancer Therapy. Molecular Cancer, 23(1): 110.
Chang M, Gao F, Pontigon D, et al., 2023, Bioorthogonal PROTAC Prodrugs Enabled by On-Target Activation. Journal of the American Chemical Society, 145(25): 14155–14163.
Gu Y, Dong B, He X, et al., 2023, The Challenges and Opportunities of αvβ3-Based Therapeutics in Cancer: From Bench to Clinical Trials. Pharmacological Research, 189: 106694.
Teng X, Zhao X, Dai Y, et al., 2024, ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy. Journal of the American Chemical Society, 146(40): 27382–27391.
Cornu M, Lemaitre T, Kieffer C, et al., 2025, PROTAC 2.0: Expanding the Frontiers of Targeted Protein Degradation. Drug Discovery Today, 2025: 104376.
Liu J, Chen H, Ma L, et al., 2020, Light-Induced Control of Protein Destruction by Opto-PROTAC. Science Advances, 6(8): eaay5154.
Xue G, Wang K, Zhou D, et al., 2019, Light-Induced Protein Degradation with Photocaged PROTACs. Journal of the American Chemical Society, 141(46): 18370–18374.
Naro Y, Darrah K, Deiters A, 2020, Optical Control of Small Molecule-Induced Protein Degradation. Journal of the American Chemical Society, 142(5): 2193–2197.
Weng W, Xue G, Pan Z, 2024, Development of Visible-Light-Activatable Photocaged PROTACs. European Journal of Medicinal Chemistry, 265: 116062.
Yang C, Yang Y, Li Y, et al., 2022, Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors. Journal of the American Chemical Society, 145(1): 385–391.
Hall W, Paulson E, Li X, et al., 2022, Magnetic Resonance Linear Accelerator Technology and Adaptive Radiation Therapy: An Overview for Clinicians. CA: A Cancer Journal for Clinicians, 72(1): 34–56.
Cheng J, Zhang J, He S, et al., 2024, Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD⁺. Angewandte Chemie International Edition, 63(12): e202315997.
Gardell S, Hopf M, Khan A, et al., 2019, Boosting NAD⁺ with a Small Molecule That Activates NAMPT. Nature Communications, 10(1): 3241.
Dwyer B, Wang C, Abegg D, et al., 2021, Chemoproteomics-Enabled De Novo Discovery of Photoswitchable Carboxylesterase Inhibitors for Optically Controlled Drug Metabolism. Angewandte Chemie International Edition, 60(6): 3071–3079.
Liang C, Zheng Q, Luo T, et al., 2022, Enzyme-Catalyzed Activation of Pro-PROTAC for Cell-Selective Protein Degradation. CCS Chemistry, 4(12): 3809–3819.
Beaver S, Mesa-Torres N, Pey A, et al., 2019, NQO1: A Target for the Treatment of Cancer and Neurological Diseases, and a Model to Understand Loss of Function Disease Mechanisms. Biochimica et Biophysica Acta – Proteins and Proteomics, 1867(7–8): 663–676.
Kamaly N, Yameen B, Wu J, et al., 2016, Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release. Chem Rev, 116(4): 2602–2663.
Xie B, Yin Z, Hu Z, et al., 2023, Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer in Vitro and in Vivo. J Med Chem, 66(10): 6631–6651.
Zhou Z, Fan H, Yu D, et al., 2023, Glutathione-Responsive PROTAC for Targeted Degradation of ERα in Breast Cancer Cells. Bioorg Med Chem, 96: 117526.
Bartoszewski R, Moszyńska A, Serocki M, et al., 2019, Primary Endothelial Cell–Specific Regulation of Hypoxia-Inducible Factor (HIF)-1 and HIF-2 and Their Target Gene Expression Profiles During Hypoxia. FASEB J, 33(7): 7929.
Cheng W, Wang S, Yang Z, et al., 2019, Design, Synthesis, and Biological Study of 4-[(2-Nitroimidazole-1 H-Alkyloxyl) Aniline]-Quinazolines as EGFR Inhibitors Exerting Cytotoxicities Both Under Normoxia and Hypoxia. Drug Des Devel Dev Ther, 2019: 3079–3089.
Cheng W, Li S, Wen X, et al., 2021, Development of Hypoxia-Activated PROTAC Exerting a More Potent Effect in Tumor Hypoxia Than in Normoxia. Chem Commun, 57(95): 12852–12855.
Yu H, Jin F, Liu D, et al., 2020, ROS-Responsive Nano-Drug Delivery System Combining Mitochondria-Targeting Ceria Nanoparticles with Atorvastatin for Acute Kidney Injury. Theranostics, 10(5): 2342.
Yao Q, Wu Z, Li J, et al., 2025, Reactive Oxygen Species-Instructed Supramolecular Assemblies Enable Bioorthogonally Activatable Protein Degradation for Pancreatic Cancer. J Am Chem Soc, 147(21): 18208–18218.
Teicher B, Morris J, 2022, Antibody-Drug Conjugate Targets, Drugs, and Linkers. Curr Cancer Drug Targets, 22(6): 463–529.
Vartak R, Deore B, Sanhueza C A, et al., 2023, Cetuximab-Based PROteolysis Targeting Chimera for Effectual Downregulation of NSCLC with Varied EGFR Mutations. Int J Biol Macromol, 252: 126413.
Pillow T, Adhikari P, Blake R, et al., 2020, Antibody Conjugation of a Chimeric BET Degrader Enables In Vivo Activity. ChemMedChem, 15(1): 17–25.
Dragovich P, Adhikari P, Blake R, et al., 2020, Antibody-Mediated Delivery of Chimeric Protein Degraders Which Target Estrogen Receptor Alpha (ERα). Bioorg Med Chem Lett, 30(4): 126907.
Liu J, Chen H, Liu Y, et al., 2021, Cancer Selective Target Degradation by Folate-Caged PROTACs. J Am Chem Soc, 143(19): 7380–7387.
Ye M, Hu J, Peng M, et al., 2012, Generating Aptamers by Cell-SELEX for Applications in Molecular Medicine. Int J Mol Sci, 13(3): 3341–3353.
Kong L, Meng F, Zhou P, et al., 2024, An Engineered DNA Aptamer-Based PROTAC for Precise Therapy of p53-R175H Hotspot Mutant-Driven Cancer. Sci Bull, 69(13): 2122–2135.
Chiang Y, Chien Y, Lin Y, et al., 2021, The Function of the Mutant p53-R175H in Cancer. Cancers, 13(16): 4088.