{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T09:42:14Z","timestamp":1785231734546,"version":"3.55.0"},"reference-count":23,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"publisher","award":["21K09347"],"award-info":[{"award-number":["21K09347"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB\u20101\/androgen receptor (AR) signaling. PMD\u2010026, an oral first\u2010in\u2010class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD\u2010026 on YB\u20101\/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration\u2010resistant prostate cancer 22Rv1 cells that express high\u2010level AR variants were used in this study. The effect of PMD\u2010026 on YB\u20101\/AR signaling was investigated by quantitative real\u2010time PCR and western blot analysis. The effects of PMD\u2010026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD\u2010026 decreased YB\u20101 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD\u2010026 suppressed cell proliferation alone and in combination with the second\u2010generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2\/M arrest. In a mouse xenograft model, PMD\u2010026 suppressed tumor growth, and the combination of PMD\u2010026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD\u2010026 and the combination effect with the antiandrogen enzalutamide in castration\u2010resistant prostate cancer. These findings warrant a clinical trial of PMD\u2010026 in prostate cancer patients.<\/jats:p>","DOI":"10.1111\/cas.15280","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T08:38:37Z","timestamp":1643963917000},"page":"1731-1738","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["An oral first\u2010in\u2010class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer"],"prefix":"10.1111","volume":"113","author":[{"given":"Miho","family":"Ushijima","sequence":"first","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3306-4858","authenticated-orcid":false,"given":"Masaki","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Kashiwagi","sequence":"additional","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Inokuchi","sequence":"additional","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Eto","sequence":"additional","affiliation":[{"name":"Department of Urology Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/iju.13091"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S306345"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/JU.0000000000001767"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-11-0018"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.07.011"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-12-0232"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10300"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.1485.3.11"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1082"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.617"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-11-0017"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-3705"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djw005"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.22813"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2009.12.010"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.1027.65.3"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0106"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","unstructured":"DunnSE JayanthanA HuynhM et al.PMD\u2010026 a first\u2010in\u2010class oral p90 ribosomal S6 kinase (RSK) inhibitor for triple\u2010negative breast cancer (TNBC). San Antonio Breast Cancer Symposium.2019; P3\u201010\u201010.","DOI":"10.1158\/1538-7445.SABCS19-P3-10-10"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","unstructured":"BeeramM WangJS MinaLA et al.A first\u2010in\u2010human Phase 1\/1b multicenter open\u2010label dose escalation study to assess safety and tolerability of PMD\u2010026 a first\u2010in\u2010class oral RSK inhibitor in metastatic breast cancer patients. San Antonio Breast Cancer Symposium.2020; PS11\u201033.","DOI":"10.1158\/1538-7445.SABCS20-PS11-33"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1809"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00300240"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","unstructured":"RamosJW SiS FujiiT et al.Targeting B\u2010RAF and checkpoint inhibitor resistant melanoma with RSK inhibitor PMD\u2010026 in pre\u2010clinical models. 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