Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties
Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties
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微管蛋白秋水仙碱位点结合剂 LL01 在体外和体内均表现出有效的抗肿瘤功效，并具有合适的药物样特性
DOI：
10.1007/s10637-019-00753-z
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发表时间：
2019-03
影响因子：
3.4
通讯作者：
Zhao-Peng Liu
中科院分区：
文献类型：
--
作者：
Jing-De Wu;Ying-Jie Cui;Yi-Gang Zhou;Long-Qian Tang;Cheng-Mei Zhang;Zhao-Peng Liu
通过合理的药物设计，我们先前确定了吲哚拉唑衍生物2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1，4-dihydroindeno[1，2-c]pyrazol-7-yloxy)acetamide(LL01)是一种针对微管蛋白秋水仙素结合部位的有效的微管蛋白聚合抑制物。在本研究中，我们进一步证明了LL01不是P-gp底物。它能有效地抑制多种肿瘤细胞的生长，包括那些具有多药耐药的肿瘤细胞，其GI50值在低纳摩尔范围内。体外肝微球稳定性实验表明，LL01在人、小鼠和大鼠肝微球中具有中等稳定性，在狗体内有较快的代谢。给SD雄性大鼠单次口服LL01 10 mg/kg后，LL01具有良好的PK特性，平均生物利用度为41%。在人肝癌移植瘤中，口服LL01 25 mg/kg/d和12.5 mg/kg/d的抑瘤率分别为61.27%和43.74%，明显优于阳性药物索拉非尼(29.45%；30 mg/kg/d)。因此，LL01有可能成为进一步研究肝细胞癌治疗的候选药物。
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 GI50values 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.
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影响因子：
13.3
作者：
Stanton, Richard A.;Gernert, Kim M.;Nettles, James H.;Aneja, Ritu
通讯作者：
Aneja, Ritu
影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
5.1
作者：
Marrero, Jorge A;Pelletier, Shawn
通讯作者：
Pelletier, Shawn
影响因子：
1.5
作者：
Gilles, HoChong;Garbutt, Tonora;Landrum, Jasmine
通讯作者：
Landrum, Jasmine
DOI：
10.1016/s0015-6264(78)80335-6
发表时间：
1986
期刊：
The New Zealand medical journal
影响因子：
--
作者：
D. Woodfield
通讯作者：
D. Woodfield