{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T01:46:53Z","timestamp":1782697613869,"version":"3.54.5"},"reference-count":35,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,6,26]]},"abstract":"<jats:p>Ribosomal S6 kinase (RSK2) is regarded as an important target for the treatment of breast and ovarian cancers. However, most reported RSK2 inhibitors suffer from insufficient selectivity and unfavorable pharmacokinetic properties due to their similar chemical scaffolds. Therefore, the discovery of novel RSK2 inhibitors with high potency, selectivity, and desirable drug\u2010like properties remains highly desirable. In this work, we established a virtual screening workflow combining pharmacophore modeling, molecular docking, and molecular dynamics simulations. By screening the Chemdiv database (1.6 million compounds), 39 potential RSK2 inhibitors were obtained. Further phenotypic screening identified compound M39 as a promising cell\u2010active RSK2 inhibitor. Surface plasmon resonance assays verified that M39 binds to RSK2 with a Kd value of 156\u2009nM. M39 inhibits the catalytic activity of RSK2 by suppressing YB1 phosphorylation and shows stronger anti\u2010tumor activity than the control LJH685 in breast and ovarian cancer cells. In summary, M39 features a unique chemical scaffold and serves as a promising lead compound for further optimization, as well as a useful chemical tool for exploring the biological functions of RSK2.<\/jats:p>","DOI":"10.1002\/cmdc.70293","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T03:36:01Z","timestamp":1782531361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a New Scaffold RSK2 Inhibitor With Virtual and Phenotypical Screening"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9443-2521","authenticated-orcid":false,"given":"Nan","family":"Feng","sequence":"first","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongru","family":"Ning","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2188-0110","authenticated-orcid":false,"given":"Keyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, West China Hospital Sichuan University  Chengdu P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1413-7804","authenticated-orcid":false,"given":"Shilong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Xiangya Hospital Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-4036","authenticated-orcid":false,"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, West China Hospital Sichuan University  Chengdu P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1367-2677","authenticated-orcid":false,"given":"Youchao","family":"Deng","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-3785","authenticated-orcid":false,"given":"Dongsheng","family":"Cao","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20110289"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710756114"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2215"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-13-0595"},{"key":"e_1_2_11_6_1","first-page":"1402","article-title":"Y\u2010Box\u2010Binding Protein 1 (YB\u20101) and Its Functions","volume":"76","author":"Eliseeva I. A.","year":"2011","journal-title":"Biochemistry"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2020.1818067"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01677-12"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.950571"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-016-0880-z"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2509"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.08.050"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5443.1358"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2741\/3003"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.312413"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-101512-122347"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104699"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.08.003"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00998-08"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.1027.65.3"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol0500463"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2006.05.009"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20061088"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/1074248415591700"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-006-9087-6"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2005.10.005"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.01.058"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm051256o"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01830"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab255"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz519"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.189365"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbad461"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01447-0"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2020.1709824"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2012.08.024"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70293","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70293","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T01:42:58Z","timestamp":1782697378000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":35,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2026,6,26]]}},"alternative-id":["10.1002\/cmdc.70293"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70293","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"assertion":[{"value":"2026-03-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70293"}}