{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:58:29Z","timestamp":1792799909935,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T00:00:00Z","timestamp":1668816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"DoD Prostate cancer ideal award","doi-asserted-by":"publisher","award":["PC190327"],"award-info":[{"award-number":["PC190327"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"DoD Prostate cancer ideal award","doi-asserted-by":"publisher","award":["PJT156150"],"award-info":[{"award-number":["PJT156150"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"DoD Prostate cancer ideal award","doi-asserted-by":"publisher","award":["PTJ178063"],"award-info":[{"award-number":["PTJ178063"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"DoD Prostate cancer ideal award","doi-asserted-by":"publisher","award":["MOP-137007"],"award-info":[{"award-number":["MOP-137007"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canadian Institute of Health Research (CIHR)","award":["PC190327"],"award-info":[{"award-number":["PC190327"]}]},{"name":"Canadian Institute of Health Research (CIHR)","award":["PJT156150"],"award-info":[{"award-number":["PJT156150"]}]},{"name":"Canadian Institute of Health Research (CIHR)","award":["PTJ178063"],"award-info":[{"award-number":["PTJ178063"]}]},{"name":"Canadian Institute of Health Research (CIHR)","award":["MOP-137007"],"award-info":[{"award-number":["MOP-137007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Lin28 is a pluripotency factor that regulates cancer cell stem-like phenotypes to promote cancer development and therapy-resistant tumor progression. It acts through its cold shock domain and zinc knuckle domain (ZKD) to interact with the Let-7 pre-microRNA and block Let-7 biosynthesis. Chemical inhibition of Lin28 from interacting with Let-7 presents a therapeutic strategy for cancer therapy. Herein, we present the computer-aided development of small molecules by in silico screening 18 million compounds from the ZINC20 library, followed by the biological validation of 163 predicted compounds to confirm 15 new Lin28 inhibitors. We report three lead compounds, Ln7, Ln15, and Ln115, that target the ZKD of both Lin28A and Lin28B isoforms and block Lin28 from binding Let-7. They restore Let-7 expression and suppress tumor oncogenes such as SOX2 in cancer cells and show strong inhibitory effects on cancer cell stem-like phenotypes. However, minimal impacts of these compounds were observed on Lin28-negative cells, confirming the on-target effects of these compounds. We conclude from this study the discovery of several new Lin28 inhibitors as promising candidate compounds that warrant further drug development into potential anticancer therapies.<\/jats:p>","DOI":"10.3390\/cancers14225687","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T04:13:36Z","timestamp":1669004016000},"page":"5687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1707-9304","authenticated-orcid":false,"given":"Mariia","family":"Radaeva","sequence":"first","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hao","family":"Ho","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xie","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4126-1170","authenticated-orcid":false,"given":"Joseph","family":"Lee","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangliang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8665-8641","authenticated-orcid":false,"given":"Nada","family":"Lallous","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Cherkasov","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-3371","authenticated-orcid":false,"given":"Xuesen","family":"Dong","sequence":"additional","affiliation":[{"name":"The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1158\/0008-5472.CAN-14-2215","article-title":"Lin28B\/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State","volume":"75","author":"Chien","year":"2015","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5338","DOI":"10.1172\/JCI135373","article-title":"LIN28B promotes the development of neuroendocrine prostate cancer","volume":"130","author":"Lovnicki","year":"2020","journal-title":"J. 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