{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:22:09Z","timestamp":1783012929655,"version":"3.54.6"},"reference-count":69,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["NRF\u20102023R1A2C1004260"],"award-info":[{"award-number":["NRF\u20102023R1A2C1004260"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["NRF\u20102023R1A2C1006689"],"award-info":[{"award-number":["NRF\u20102023R1A2C1006689"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. RYK, an atypical receptor\u2010like tyrosine kinase, has emerged as a potential regulator of tumour signalling, but its role in PDAC remains poorly understood. This study aimed to evaluate the anticancer potential of BJ\u20102412, a novel sunitinib analogue with RYK\u2010inhibitory activity, and to elucidate the functional relevance of RYK in PDAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>BJ\u20102412 was synthesized by introducing a 2,4\u2010dimethylpyridin\u20103\u2010ol moiety into sunitinib. Its anticancer activity was assessed in PDAC cell lines and mouse tumour models. Mechanistic studies included RTK phosphorylation profiling, RYK knockdown via siRNA, co\u2010immunoprecipitation, immunoblotting of downstream effectors, and analyses of apoptosis, invasion, and macrophage phenotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>BJ\u20102412 inhibited RYK phosphorylation by disrupting its interaction with EGFR. While RYK knockdown and BJ\u20102412 had minimal effects on proliferation, both impaired cancer cell survival, including that of cancer stem cells. We identified RYK as a GSK\u20103\u03b2 activator that antagonizes canonical WNT signalling and RTK\u2010mediated GSK\u20103\u03b2 inhibition. BJ\u20102412 inactivated GSK\u20103\u03b2 and reduced Sonic Hedgehog (Shh) and GLI1 expression. BJ\u20102412\u2010induced up\u2010regulation of WNT5A, cancer cell\u2010selective apoptosis, M1\u2010macrophage polarization, as well as down\u2010regulation of MMPs and CTSS, were reversed by recombinant Shh. Finally, BJ\u20102412 suppressed tumour growth, invasion, and metastasis in xenograft and allograft mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>These findings identify RYK as a GSK\u20103\u03b2 activator and a therapeutic vulnerability in PDAC. BJ\u20102412 demonstrates therapeutic potential by targeting this pathway and remodelling the tumour microenvironment, offering a multifaceted strategy against PDAC progression and resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70455","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:40:18Z","timestamp":1776991218000},"page":"4196-4214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic targeting of GSK\u20103\u03b2 activation by the tyrosine kinase RYK in pancreatic ductal adenocarcinoma with BJ\u20102412, a novel sunitinib analogue"],"prefix":"10.1111","volume":"183","author":[{"given":"Kiran","family":"Yadav","sequence":"first","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana","family":"Ghimire","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Mishra","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunji","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy Kyungsung University  Busan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawon","family":"Bae","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae\u2010Hoon","family":"Chang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong\u2010Seon","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0824-8532","authenticated-orcid":false,"given":"Jung\u2010Ae","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy Yeungnam University  Gyeongsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70234"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70233"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70229"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.220"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080926"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2004.23590.x"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215305"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj20031259"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012260318979"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/378785a0"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17441"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1990"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.22.3499"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201100201"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.08.028"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232214133"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0336-9"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1068"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-016-4898-0"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06557"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1770"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/78099"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2020.7817"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.24.11818"},{"key":"e_1_2_12_26_1","unstructured":"Howlader N. 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