{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:39:30Z","timestamp":1760236770783,"version":"build-2065373602"},"reference-count":17,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803437","82173690","81825020"],"award-info":[{"award-number":["81803437","82173690","81825020"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project","award":["21S11907900","20S11901000"],"award-info":[{"award-number":["21S11907900","20S11901000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure\u2013activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.<\/jats:p>","DOI":"10.3390\/molecules27010203","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T23:31:35Z","timestamp":1640820695000},"page":"203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, and Structure\u2013Activity Relationship Study of Potent MAPK11 Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Mengdie","family":"Gong","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2605-8265","authenticated-orcid":false,"given":"Mingyan","family":"Tu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongxia","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honglin","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"},{"name":"Jiangzhong Pharmaceutical Co., Ltd., Nanchang 330096, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenjiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-237X","authenticated-orcid":false,"given":"Shiliang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: From molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S1474-4422(17)30280-6","article-title":"Therapies targeting DNA and RNA in Huntington\u2019s disease","volume":"16","author":"Wild","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s12041-018-0957-1","article-title":"Huntington\u2019s disease: The coming of age","volume":"97","author":"Pandey","year":"2018","journal-title":"J. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1517\/14728222.7.2.187","article-title":"MAPKs: New targets for neurodegeneration","volume":"7","author":"Harper","year":"2003","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/cr.2017.113","article-title":"Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington\u2019s disease models","volume":"27","author":"Yu","year":"2017","journal-title":"Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17920","DOI":"10.1074\/jbc.271.30.17920","article-title":"Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta)","volume":"271","author":"Jiang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19509","DOI":"10.1074\/jbc.272.31.19509","article-title":"p38-2, a novel mitogen-activated protein kinase with distinct properties","volume":"272","author":"Stein","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1107\/S090744490901600X","article-title":"The three-dimensional structure of MAP kinase p38beta: Different features of the ATP-binding site in p38beta compared with p38alpha","volume":"65","author":"Patel","year":"2009","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1080\/13543776.2020.1749263","article-title":"An updated patent review of p38 MAP kinase inhibitors (2014\u20132019)","volume":"30","author":"Haller","year":"2020","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.cellsig.2007.12.003","article-title":"Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: A MLK-3-MKK7-dependent mechanism","volume":"20","author":"Muniyappa","year":"2008","journal-title":"Cell. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/S0140-6736(14)60417-7","article-title":"Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: A randomised phase 2 trial","volume":"384","author":"Newby","year":"2014","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6743","DOI":"10.1074\/jbc.M112.425553","article-title":"LY2228820 dimesylate, a selective inhibitor of p38 mitogen-activated protein kinase, reduces angiogenic endothelial cord formation in vitro and in vivo","volume":"288","author":"Tate","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.bcp.2008.10.032","article-title":"Inhibition of pro-inflammatory cytokine production by the dual p38\/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling","volume":"77","author":"Gruenbaum","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1021\/ml2001455","article-title":"The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor","volume":"2","author":"Duffy","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nchembio.761","article-title":"Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor","volume":"8","author":"Koeberle","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1021\/jm300327h","article-title":"Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase","volume":"55","author":"Koeberle","year":"2012","journal-title":"J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:40Z","timestamp":1760169340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,29]]},"references-count":17,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["molecules27010203"],"URL":"https:\/\/doi.org\/10.3390\/molecules27010203","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,12,29]]}}}