{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:02:07Z","timestamp":1791460927322,"version":"4.3.4"},"reference-count":93,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273763"],"award-info":[{"award-number":["82273763"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473770"],"award-info":[{"award-number":["82473770"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2025QC1383"],"award-info":[{"award-number":["ZR2025QC1383"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medicinal Research Reviews"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The covalent recruitment of E3 ubiquitin ligases is a rapidly advancing strategy in targeted protein degradation (TPD). While traditional non\u2010covalent PROTACs and molecular glues operate through transient binding equilibria that can limit catalytic efficiency, covalent degraders form irreversible bonds with E3 ligases, thereby stabilizing ternary complexes, enhancing degradation kinetics, and enabling a \u201cpre\u2010assembly\u201d mechanism in which the degrader remains bound to the E3 ligase after each degradation event to facilitate multi\u2010turnover catalysis. Recent advances in chemoproteomic platforms have enabled the systematic identification of ligandable amino acid residues across the E3 ligase landscape, transforming degrader discovery from serendipitous observation to rational structure\u2010guided design. This technological revolution has dramatically expanded the repertoire of recruitable E3 ligases beyond traditional candidates such as CRBN and VHL, thereby overcoming resistance mechanisms and enabling access to historically undruggable targets. This review systematically outlines the design principles of covalent E3\u2010targeting PROTACs and contrasts them with covalent E3\u2010targeting molecular glues. The latter achieve potent degradation through either template\u2010assisted covalent modification or the incorporation of transplantable electrophilic handles. We summarize representative covalent E3\u2010recruiting degraders, focusing on their design principles, mechanistic insights, and therapeutic potential. We further discuss key challenges and future directions, particularly the imperative to broaden E3 ligase coverage and diversify warhead chemistry, aiming to provide valuable insights for the development of covalent protein degraders.<\/jats:p>","DOI":"10.1002\/med.70111","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:44:09Z","timestamp":1791459849000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Covalent Recruitment of E3 Ligases: A New Path for Rational Design of Protein Degraders"],"prefix":"10.1002","author":[{"given":"Ziyan","family":"Yu","sequence":"first","affiliation":[{"name":"International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy Jinan University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5725-0391","authenticated-orcid":false,"given":"Man","family":"Tong","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7364-4876","authenticated-orcid":false,"given":"Lanlan","family":"Zang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Linyi People's Hospital Shandong Second Medical University Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5778-0840","authenticated-orcid":false,"given":"Jie","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Linyi People's Hospital Shandong Second Medical University Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7931-6873","authenticated-orcid":false,"given":"Xiaoyun","family":"Lu","sequence":"additional","affiliation":[{"name":"International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy Jinan University Guangzhou Guangdong China"},{"name":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2020.07.020"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.141230798"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00895"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1887"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c02076"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01882"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00148A"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.1c00464"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2023.09.003"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00817-8"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2024.04.002"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.22101"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.22113"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2024.12.006"},{"key":"e_1_2_9_16_1","first-page":"1","article-title":"Induced Proximity\u2010Based Therapeutic Modalities","volume":"25","author":"King E. A.","year":"2025","journal-title":"Nature Reviews Drug Discovery"},{"issue":"1","key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1021\/acs.chemrev.4c00570","article-title":"Covalent Proximity Inducers","volume":"125","author":"London N.","year":"2024","journal-title":"Chemical Reviews"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00362G"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.03.005"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja311795d"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b01083"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0279-5"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c00990"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c08964"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c03980"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0304-8"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.01.005"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.01.004"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-72491-9"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02123"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CB00103B"},{"issue":"1","key":"e_1_2_9_32_1","doi-asserted-by":"crossref","first-page":"7908","DOI":"10.1038\/s41467-023-43657-6","article-title":"Discovery of a Drug\u2010Like, Natural Product\u2010Inspired DCAF11 Ligand Chemotype","volume":"14","author":"Xue G.","year":"2023","journal-title":"Nature Communications"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b13193"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci5002058"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196515"},{"issue":"31","key":"e_1_2_9_36_1","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1021\/acs.biochem.1c00301","article-title":"Electrophilic Screening Platforms for Identifying Novel Covalent Ligands for E3 Ligases","volume":"60","author":"Zheng S.","year":"2021","journal-title":"Biochemistry"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijch.202200100"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1155\/2002\/505397"},{"issue":"7","key":"e_1_2_9_39_1","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/anie.201912075","article-title":"Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome","volume":"59","author":"Zanon P. R. A.","year":"2020","journal-title":"Angewandte Chemie International Edition"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.11.015"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.4c00668"},{"key":"e_1_2_9_42_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/978-1-0716-3354-0_11","article-title":"Immunoprecipitation\u2010Mass Spectrometry (IP\u2010MS) of Protein\u2010Protein Interactions of Nuclear\u2010Localized Plant Proteins","volume":"2698","author":"Smaczniak C.","year":"2023","journal-title":"Methods in Molecular Biology"},{"key":"e_1_2_9_43_1","article-title":"Label\u2010Free Immunoprecipitation Mass Spectrometry Workflow for Large\u2010Scale Nuclear Interactome Profiling","volume":"153","author":"Guard S. E.","year":"2019","journal-title":"Journal of Visualized Experiments : JoVE"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1716"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-022X(01)00213-5"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-119-6_12"},{"key":"e_1_2_9_47_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/978-1-4939-7033-9_17","volume-title":"Bacterial Protein Secretion Systems: Methods and Protocols","author":"Lin J.\u2010S.","year":"2017"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114321"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106637"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjy085"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.101304.124125"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.034"},{"issue":"12","key":"e_1_2_9_53_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S1875-5364(23)60500-X","article-title":"Utilizing Natural Products as New E3 Ligase Ligands for Targeted Protein Degradation","volume":"21","author":"Gong Y.","year":"2023","journal-title":"Chinese Journal of Natural Medicines"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.33"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2020.00018"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00387B"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr900267p"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.2144\/05384TE01"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CC04661F"},{"issue":"1","key":"e_1_2_9_60_1","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/s41467-022-28520-4","article-title":"The AUTOTAC Chemical Biology Platform for Targeted Protein Degradation Via the Autophagy\u2013Lysosome System","volume":"13","author":"Ji C. H.","year":"2022","journal-title":"Nature Communications"},{"issue":"14","key":"e_1_2_9_61_1","doi-asserted-by":"crossref","first-page":"8176","DOI":"10.1021\/jacs.3c01421","article-title":"Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2","volume":"145","author":"Hanley R. P.","year":"2023","journal-title":"Journal of the American Chemical Society"},{"issue":"1","key":"e_1_2_9_62_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41589-021-00898-0","article-title":"A Chemical Probe Targeting the PWWP Domain Alters NSD2 Nucleolar Localization","volume":"18","author":"Dilworth D.","year":"2022","journal-title":"Nature Chemical Biology"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.16.7120-7136.2005"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-024-01660-y"},{"issue":"28","key":"e_1_2_9_65_1","doi-asserted-by":"crossref","first-page":"10571","DOI":"10.1021\/jacs.1c05269","article-title":"Primary Amine Tethered Small Molecules Promote the Degradation of X\u2010Linked Inhibitor of Apoptosis Protein","volume":"143","author":"den Besten W.","year":"2021","journal-title":"Journal of the American Chemical Society"},{"issue":"1","key":"e_1_2_9_66_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41589-019-0414-3","article-title":"Molecular Glue Concept Solidifies","volume":"16","author":"Baek K.","year":"2020","journal-title":"Nature Chemical Biology"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00339B"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-024-01668-4"},{"key":"e_1_2_9_69_1","doi-asserted-by":"crossref","unstructured":"Z.Zhuang W. S.Byun Z.Kozicka et al. \u201cDiscovery of Electrophilic Degraders That Exploit SNAr Chemistry \u201d preprint bioRxiv September 27 2024 https:\/\/doi.org\/10.1101\/2024.09.25.615094.","DOI":"10.1101\/2024.09.25.615094"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c11003"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.4c00286"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.5c00959"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c18083"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202508538"},{"key":"e_1_2_9_75_1","unstructured":"R. A.Blake P.Dragovich L. J.Gazzard et al. Inventors; Genentech Inc. F. Hoffmann\u2010La Roche AG Assignee. Preparation of tert\u2010butyl (S)\u20102\u2010(4\u2010(phenyl)\u20106H\u2010thieno[3 2\u2010f][1 2 4]triazolo[4 3\u2010a][1 4]diazepin\u20106\u2010yl)acetate Derivatives and Related Compounds as Bromodomain BRD4 Inhibitors for the Treatment of Cancer. US patent WO20200559762020."},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.2c00747"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116904"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c06622"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c09857"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.2c01317"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2374-x"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00722"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.117166"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11080771"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6c00889"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202504813"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.181341498"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05333-5"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1582"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400029"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3854"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00542-z"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17997-6"},{"key":"e_1_2_9_94_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b13907"}],"container-title":["Medicinal Research Reviews"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/med.70111","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/med.70111","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/med.70111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:44:14Z","timestamp":1791459854000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/med.70111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":93,"alternative-id":["10.1002\/med.70111"],"URL":"https:\/\/doi.org\/10.1002\/med.70111","archive":["Portico"],"relation":{},"ISSN":["0198-6325","1098-1128"],"issn-type":[{"value":"0198-6325","type":"print"},{"value":"1098-1128","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"med.70111"}}