{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:29:38Z","timestamp":1791523778304,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M703348"],"award-info":[{"award-number":["2021M703348"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22107101"],"award-info":[{"award-number":["22107101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021B1515420002"],"award-info":[{"award-number":["2021B1515420002"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2024,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1\u2010targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis\u2010targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, <jats:bold>KW0113<\/jats:bold> (DC<jats:sub>50<\/jats:sub>=643\/899\u2005nM in MV4\u201311\/MOLM\u201013 cells) exhibited optimal DNMT1 degradation. <jats:bold>KW0113<\/jats:bold> induced DNMT1\u2010selective degradation in a dose\u2010 and time\u2010dependent manner through VHL engagement. Moreover, <jats:bold>KW0113<\/jats:bold> inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor\u2010suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1\u2010targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1\u2010related studies.<\/jats:p>","DOI":"10.1002\/cmdc.202400467","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T10:28:59Z","timestamp":1726828139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein"],"prefix":"10.1002","volume":"19","author":[{"given":"Huihui","family":"Wang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Nanchang University  Nanchang 330031 China"},{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoliang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences  Guangzhou 510000 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghao","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"},{"name":"Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjie","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"},{"name":"Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangyi","family":"Zong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences  Guangzhou 510000 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dounan","family":"Xu","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Nanchang University  Nanchang 330031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqian","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences  Guangzhou 510000 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3834-3784","authenticated-orcid":false,"given":"Mingliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica Chinese Academy of Sciences  Zhongshan 528400 China"},{"name":"University of Chinese Academy of Sciences  Beijing 100049 China"},{"name":"Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,7]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019505"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.93"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.03.003"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00357-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.208108.116"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.24"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.05.015"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1698"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2180"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2013.42"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0266-5"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.02.006"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2783"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23607"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.12.029"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo034248t"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgi206"},{"issue":"22","key":"e_1_2_10_19_1","first-page":"7563","volume":"63","author":"Fang M. Z.","year":"2003","journal-title":"Cancer Res."},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3669"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm050844z"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2079640"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00249-x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2022.03.009"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00890"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/narcan\/zcad022"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34779-4"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes9120620"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi8011725"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks031"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.2217\/epi-2022-0035"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/77023"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.7.2.18756"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0307-289"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00482"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01348"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.4.1407-1418.2000"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz430"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0406771101"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194955"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13071070"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2013.10.006"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2538"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2021.10.037"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2021.05.002"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2022.2099578"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202400467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:04:58Z","timestamp":1760288698000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202400467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,7]]},"references-count":47,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2024,12,16]]}},"alternative-id":["10.1002\/cmdc.202400467"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202400467","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,7]]},"assertion":[{"value":"2024-06-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202400467"}}