{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:45:52Z","timestamp":1789749952478,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) is a typically fatal malignancy with limited treatment options and poor survival rates, despite recent FDA approvals of newer treatment options. We aim to address this unmet need by using a proprietary computational drug discovery platform that identifies drug candidates with the potential to advance rapidly and successfully through preclinical studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated an in silico model of HCC biology to identify the top 10 small molecules with predicted efficacy. The most promising candidate, CYT997, was tested for its in\u00a0vitro effects on cell viability and cell death, colony formation, cell cycle changes, and cell migration\/invasion in HCC cells. We used an HCC patient\u2010derived xenograft (PDX) mouse model to assess its in\u00a0vivo efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CYT997 was significantly more cytotoxic against HCC cells than against primary human hepatocytes, and sensitized HCC cells to sorafenib. It arrested cell cycle at the G2\/M phase with associated up\u2010regulations of p21, p\u2010MEK1\/2, p\u2010ERK, and down\u2010regulation of cyclin B1. Cell apoptosis and senescence\u2010like morphology were also observed. CYT997 inhibited HCC cell migration and invasion, and down\u2010regulated the expressions of acetylated tubulins, \u03b2\u2010tubulin, glypican\u20103 (GPC3), \u03b2\u2010catenin, and c\u2010Myc. In\u00a0vivo, CYT997 (20\u2009mg\/kg, three times weekly by oral gavage) significantly inhibited PDX growth, while being non\u2010toxic to mice. Immunohistochemistry confirmed the down\u2010regulation of GPC3, c\u2010Myc, and Ki\u201067, supporting its anti\u2010proliferative effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CYT997 is a potentially efficacious and non\u2010toxic drug candidate for HCC therapy. Its ability to down\u2010regulate GPC3, \u03b2\u2010catenin, and c\u2010Myc highlights a novel mechanism of action.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15756","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T04:50:35Z","timestamp":1697259035000},"page":"2794-2807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification and validation of microtubule depolymerizing agent, CYT997, as a potential drug candidate for hepatocellular carcinoma"],"prefix":"10.1111","volume":"43","author":[{"given":"Faiz","family":"Ahmad","sequence":"first","affiliation":[{"name":"Asian Liver Center Department of Surgery, School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ma","sequence":"additional","affiliation":[{"name":"Asian Liver Center Department of Surgery, School of Medicine  Stanford California 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