{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:00:37Z","timestamp":1790604037375,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","issue":"40","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2R01CA220468\u201006A1"],"award-info":[{"award-number":["2R01CA220468\u201006A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cereblon (CRBN)\u2010recruiting PROTACs (proteolysis\u2010targeting chimeras) are among the most clinically advanced degraders but remain challenging to chemically modify for translation to prodrug\u2010based delivery strategies. Here, we report three orthogonal approaches\u2014triazole quaternization, tertiary\u2010amine alkylation, and installation of a hydroxyl linker\u2014that enable chemoselective, high\u2010yielding syntheses of CRBN\u2010recruiting PROTAC prodrugs. These strategies allow incorporation of self\u2010immolative linkers whose cleavage kinetics can be predictably tuned to release the parent PROTAC, which is demonstrated in the context of PEGylated macromonomer and bottlebrush prodrug macromolecular scaffolds. In multiple myeloma models, representative PROTAC\u2010bottlebrush prodrugs (PROTAC\u2010BPDs) induce cellular potency profiles that follow the designed PROTAC release rates, confirming that the observed protein degradation and cytotoxicity arise from effective prodrug linker cleavage. Collectively, this work establishes generalizable approaches for constructing prodrugs of CRBN\u2010based PROTACs, expanding the synthetic space for targeted protein degradation and providing new design principles for controlling degrader activation, selectivity, and in vivo delivery.<\/jats:p>","DOI":"10.1002\/anie.3238473","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:25:37Z","timestamp":1785936337000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generalizable Strategies for the Synthesis of Cereblon\u2010Recruiting PROTAC Prodrugs"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6335-9836","authenticated-orcid":false,"given":"Aiden X.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise M.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Xiang","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung V.\u2010T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yivan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela N.","family":"Koehler","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"},{"name":"Department of Biological Engineering Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"Center For Precision Cancer Medicine Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9157-6491","authenticated-orcid":false,"given":"Jeremiah A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000736\u20103"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2020.07.020"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3739"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.692574"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.211"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.11.031"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573\u2010021\u201000052\u20104"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116166"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196515"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201042233\u20102"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crchbi.2022.100020"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2021.707317"},{"key":"e_1_2_9_15_1","unstructured":"NJBio 2026 Targeted Protein Degraders"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2023.2187047"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.22026"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065190"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102022\u2010164772"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.5c01241"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c02221"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202107347"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.4c00298"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.022.202101529"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay5064"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b06422"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c05159"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.07.062"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00285"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201032050\u20104"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.022.202101529"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay5154"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00901"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c05036"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01846"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102910"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.574525"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.753119"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.201483"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2025.03.001"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010018\u20100055\u2010y"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201052871\u20109"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00652"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c00312"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0PY00558D"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2635"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201016\u20100038"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.04.007"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201039904\u20105"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09504"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmacrolett.8b00201"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg2239"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551\u2010018\u20100279\u2010x"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010022\u201001310\u20101"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02772-z"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma1021506"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00129320"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1039\/p29940002021"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.1965.tb02053.x"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00454"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16580"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma301874d"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmacrolett.4c00119"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15010195"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521\u20103773(20021104)41:21<4035::AID\u2010ANIE4035>3.0.CO;2\u2010I"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2025.03.001"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2020.10.001"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010018\u20100044\u2010x"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.1965.tb02053.x"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3238473","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.3238473","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.3238473","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:19:21Z","timestamp":1790601561000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.3238473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":68,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,9,28]]}},"alternative-id":["10.1002\/anie.3238473"],"URL":"https:\/\/doi.org\/10.1002\/anie.3238473","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"2026-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e3238473"}}