{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:52:55Z","timestamp":1792979575296,"version":"4.5.0"},"reference-count":57,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dean\u2019s Innovation Award, College of Pharmacy OSU"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide\u2019s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine\u2013niclosamide improves upon niclosamide\u2019s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine\u2013niclosamide in advanced HCC and in other cancers or diseases is warranted.<\/jats:p>","DOI":"10.3390\/cancers17152535","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T08:51:41Z","timestamp":1754038301000},"page":"2535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Valine\u2013Niclosamide for Treatment of Androgen Receptor Splice Variant-Positive Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3363-3253","authenticated-orcid":false,"given":"Emma J.","family":"Hoelzen","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna S.","family":"Radomska","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel K.","family":"Kulp","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeoluwa A.","family":"Adeluola","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6043-7143","authenticated-orcid":false,"given":"Lauren A.","family":"Granchie","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anees M.","family":"Dauki","sequence":"additional","affiliation":[{"name":"Exelixis Inc., Alameda, CA 94502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moray J.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4852-0596","authenticated-orcid":false,"given":"Shabber","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enming","family":"Xing","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8675-8976","authenticated-orcid":false,"given":"Min","family":"Hai","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1615-5280","authenticated-orcid":false,"given":"Mitch A.","family":"Phelps","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pui-Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8184-9190","authenticated-orcid":false,"given":"Christopher C.","family":"Coss","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s43018-022-00357-2","article-title":"Molecular Pathogenesis and Systemic Therapies for Hepatocellular Carcinoma","volume":"3","author":"Llovet","year":"2022","journal-title":"Nat. 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