化学
微管蛋白
机制(生物学)
降级(电信)
聚合
对偶(语法数字)
组合化学
生物物理学
微管
生物化学
立体化学
有机化学
细胞生物学
聚合物
艺术
电信
哲学
文学类
认识论
计算机科学
生物
作者
Sibo Wang,Jiahao Wang,Xiaohui Lu,Maosong Liu,Yue Liu,Mi Li,Xiaoyuan Kong,Lan Wu,Qi Guan,Weige Zhang
标识
DOI:10.1016/j.ejmech.2024.116458
摘要
Microtubules are recognized as one of the most vital and attractive targets in anticancer therapy. The development of novel tubulin-targeting agents with a new action mechanism is imperative. Based on the hydrophobic tagging strategy, the molecular scaffold of tirbanibulin was selected as tubulin target-binding moiety, subsequent to which a series of target compounds were rationally designed by selecting various combinations of linkers and hydrophobic tags. A set of novel molecules were synthesized and most of them exhibited potent antiproliferative activity against tumor cells in vitro. The most active compound 14b inhibited polymerization of purified recombinant tubulin and induced degradation of α- and β-tubulin in MCF-7 cells. Notably, following treatment with compound 14b, an unexpected phenomenon of "microtubules fragmentation" was observed via immunofluorescence staining. Furthermore, compound 14b possessed antitumor activity in the 4T1 allograft models with TGI of 74.27% without significant toxicity. In this work, we report the discovery of novel dual-mechanism tubulin-targeting agents.
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