秋水仙碱
化学
微管蛋白
吲哚试验
IC50型
体内
黑色素瘤
免疫系统
体外
药理学
癌症研究
立体化学
生物化学
微管
免疫学
细胞生物学
生物
内科学
医学
生物技术
作者
Yichang Ren,Yuxi Wang,Jin Liu,Ting Liu,L. Yuan,Chengyong Wu,Zichao Yang,Jianjun Chen
标识
DOI:10.1021/acs.jmedchem.3c00011
摘要
A series of novel indole analogues were discovered as colchicine-binding site inhibitors of tubulin. Among them, 3a exhibited the highest antiproliferative activity (average IC50 = 4.5 nM), better than colchicine (IC50 = 65.3 nM). The crystal structure of 3a in complex with tubulin was solved by X-ray crystallography, which explained the improved binding affinity of 3a to tubulin and thus its higher anticancer activity (IC50 = 4.5 nM) than the lead compound 12b (IC50 = 32.5 nM). In vivo, 3a (5 mg/kg) displayed significant antitumor efficacy against B16-F10 melanoma with a TGI of 62.96% and enhanced the antitumor efficacy of a small-molecule PD-1/PD-L1 inhibitor NP19 (TGI = 77.85%). Moreover, 3a potentiated the antitumor immunity of NP19 by activating the tumor immune microenvironment, as demonstrated by the increased tumor-infiltrating lymphocytes (TIL). Collectively, this work shows a successful example of crystal structure-guided discovery of a novel tubulin inhibitor 3a as a potential anticancer and immune-potentiating agent.
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