State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, Innovation Center of Nursing Research, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, Sichuan, China.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
J Med Chem. 2021 Jun 24;64(12):7963-7990. doi: 10.1021/acs.jmedchem.1c00100. Epub 2021 Jun 8.
Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure-activity relationships, and future directions of dual-target tubulin inhibitors.
微管在多种细胞功能中发挥着关键作用，包括有丝分裂、细胞信号转导和细胞器运输，这使得微管成为癌症治疗的一个重要靶点。尽管微管靶向药物在临床上取得了巨大成功，但耐药性的发展和剂量限制毒性限制了它们的临床疗效。近年来，多靶点治疗被认为是提高治疗效果的有效策略，特别是双靶点药物。在联合治疗中，微管蛋白与其他抗肿瘤药物（如受体酪氨酸激酶抑制剂、组蛋白去乙酰化酶抑制剂、DNA 损伤剂和拓扑异构酶抑制剂）的协同作用下，设计双靶点微管蛋白抑制剂被认为是克服这些限制并提高治疗效果的一种有前途的方法。在这篇观点文章中，我们讨论了双靶点微管蛋白抑制剂的合理靶标组合、设计策略、结构-活性关系以及未来方向。
