{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:24:53Z","timestamp":1787977493373,"version":"build-2784847793"},"reference-count":55,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"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":["1RF1AG064250"],"award-info":[{"award-number":["1RF1AG064250"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM128894"],"award-info":[{"award-number":["R35GM128894"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA023168"],"award-info":[{"award-number":["P30 CA023168"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA290858"],"award-info":[{"award-number":["R01CA290858"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA023168"],"award-info":[{"award-number":["CA023168"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG DMC133996"],"award-info":[{"award-number":["RSG DMC133996"]}],"id":[{"id":"10.13039\/100000048","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":[[2026,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Targeted covalent inhibitors (TCIs) are increasingly popular as drug candidates and chemical probes. Among current TCIs, the chemistry is largely limited to cysteine and lysine side chain reactivity. Here, we investigated the utility of cyclic imine Mannich electrophiles as covalent warheads to target protein tyrosine and tryptophan side chains. We characterized the intrinsic reaction rates of several cyclic imines to tyrosine and other amino acid side chains and validated reactivity using protein affinity labeling of a cyclic imine\u2010modified trimethoprim with tyrosine and tryptophan mutants of\n                    <jats:italic>E. coli<\/jats:italic>\n                    dihydrofolate reductase. To validate the utility of the approach, we appended cyclic imine warheads to a CBX8 chromodomain inhibitor to label a non\u2010conserved tyrosine, which improved both the potency and selectivity of the inhibitor for CBX8 in vitro and in cells. These findings indicate that Mannich electrophiles are promising and robust chemical warheads for tyrosine and tryptophan bioconjugation and development of covalent inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/anie.202516630","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:49:11Z","timestamp":1769665751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Covalent Protein Inhibitors via Tyrosine and Tryptophan Conjugation with Cyclic Imine Mannich Electrophiles"],"prefix":"10.1002","volume":"65","author":[{"given":"Sijie","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Hadisurya","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Purdue University  175 South University Street West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siavash Shahbazi","family":"Nia","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Andy","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"},{"name":"Department of Biochemistry Purdue University  175 South University Street West Lafayette IN 47907 USA"},{"name":"Purdue Center for Cancer Research Purdue University  201 South University Street West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Dykhuizen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"},{"name":"Purdue Center for Cancer Research Purdue University  201 South University Street West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2964-3520","authenticated-orcid":false,"given":"Casey J.","family":"Krusemark","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology Purdue University  575 Stadium Mall Drive West Lafayette IN 47907 USA"},{"name":"Purdue Center for Cancer Research Purdue University  201 South University Street West Lafayette IN 47907 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"e_1_2_5_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900107"},{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201601091"},{"key":"e_1_2_5_3_1","first-page":"38","volume":"12","author":"Ostrem J. M. L.","year":"2025","journal-title":"Annu. Rev. Cancer Biol."},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001589\u2010z"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00745"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5c00001"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2020.00280"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10930\u2010007\u20109108\u2010x"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12918\u2010016\u20100351\u20107"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb800314v"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21228776"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105038"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007140\u20106"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.1843"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5SC00408J"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7CS00220C"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201309399"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.1c01591"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00561"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201806037"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2023.2218642"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5SC02647D"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301205j"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.3286"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adp9958"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC06942J"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc300665t"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja046239n"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja031790q"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9OB01471C"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.19122500151"},{"key":"e_1_2_5_32_1","first-page":"301","volume":"30","author":"Betti M.","year":"1900","journal-title":"Gazz. Chim. Ital."},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0439017"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo8017389"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm501412a"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0491533"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/B713885G"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.3987\/COM\u201003\u20109802"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.7b05316"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.2c00633"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27051673"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25020414"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep05343"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.013179"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(19)77815\u20106"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2008.08.006"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00654"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1177\/2472555217750871"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2007"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1039\/b311203a"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/cc000058"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200500533"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.419"},{"key":"e_1_2_5_54_1","first-page":"2195","volume":"29","author":"Bates H. M.","year":"1969","journal-title":"Cancer Res."},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euprot.2015.02.002"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202516630","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202516630","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202516630","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T13:59:22Z","timestamp":1776952762000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202516630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":55,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,4,6]]}},"alternative-id":["10.1002\/anie.202516630"],"URL":"https:\/\/doi.org\/10.1002\/anie.202516630","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]},"assertion":[{"value":"2025-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e16630"}}