5-arylalkynyl-2-benzoyl thiophene: a novel microtubule inhibitor exhibits antitumor activity without neurological toxicity

作者：Zhuang, Yuxin; Yang, Guang; Wu, Shaoyu; Chen, Jianjun; Guo, Jiayin; Quan, Dongling; Zhang, Tingting; Yang, Zichao; Tan, Shaobin; Ji, Yuheng; Chen, Zhipeng^*; Lv, Lin^*

来源：American Journal of Cancer Research, 2022, 12(1): 229-+.

• Microtubule inhibitor
• breast cancer
• neurological toxicity

The composition of microtubules involving several steps, including the polymerization and depolymerization of alpha-tubulin and beta-tubulin heterodimers. Microtubule-targeting agents can increase or inhibit microtubule polymerization, thereby disrupting the dynamic process and stalling cells in G2/M phase. Microtubule-targeting agents are generally cytotoxic, which neurological toxicity being one of the significant adverse events associated. We recently reported a novel 5-arylalkynyl-2-benzoyl thiophene (PST-3) that exhibited broad-spectrum cellular cytotoxicity and in vivo potency with high safety. PST-3 was a substrate of p-gp, which could not cross the blood-brain barrier and lead to less neurotoxicity. The antitumor activities in vitro demonstrated that PST-3 combined with the colchicine-binding site on microtubule, induces morphological changes, disrupts microtubule networks, inhibits polymerization of tubulin, arrests breast cancer cells in the G2/M phase of the cell cycle and induces apoptosis. Evaluation of the antitumor effect in vivo demonstrated that PST-3 elicited MDA-MB-468 tumor %T/C of 11.75%, whereas elicited MCF7 tumor %T/C of 44.38% in breast cancer xenograft models. Besides, in vivo experiments of a higher dose (60 mg/kg) of PST 3 treatment for 21 days did not produce any significant neurotoxicity. These results provide evidence that PST-3 might possess the potential to be developed into a new microtubule inhibitor without neurological toxicity.

• 单位
  南方医科大学