标题：Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties
作者：Wu J.-D.; Cui Y.-J.; Zhou Y.-G.; Tang L.-Q.; Zhang C.-M.; Liu Z.-P.
作者机构：[Wu, J.-D] Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong U 更多
通讯作者地址：[Liu, Z.-P] Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong 更多
来源：Investigational New Drugs
关键词：Hepatocellular carcinoma; Liver microsome stability; Multidrug-resistance; Pharmacokinetics; Tubulin polymerization inhibitor
摘要：Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI 50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.