Taccalonolide Microtubule Stabilizers.
Taccalonolide Microtubule Stabilizers.
复制标题
DOI：
10.1007/978-3-030-52966-6_3
复制
发表时间：
2020
影响因子：
--
通讯作者：
Risinger AL
中科院分区：
文献类型：
--
作者：
Yee SS;Du L;Risinger AL
微管稳定剂是治疗许多实体癌的主要药物，并继续在与分子靶向抗癌剂和免疫治疗剂的联合治疗中发现效用。然而，对微管稳定剂的先天性和获得性抗性会限制其临床疗效。taccalonolides是一类独特的微管稳定剂，从植物分离的tacca规避临床相关的耐药机制。尽管最初的报告表明，taccalonolides的微管稳定活性不依赖于直接的微管蛋白结合，但其他研究已经确定，有效的C-22、C-23环氧化taccalonolides共价结合β-微管蛋白的天冬氨酸226残基，并且这种相互作用对其微管稳定活性至关重要。与其他微管稳定剂相比，taccalonolides在其对微管蛋白结构和动力学的生化作用方面具有独特的性质，从而促进不同的细胞表型。一些他卡内酯已在耐药肿瘤模型中显示出体内抗肿瘤功效，由于其不可逆的靶点接合，具有精致的效力和持久的抗肿瘤功效。最近鉴定的一个网站上的taccalonolide支架，是适合修改提供了证据的特异性taccalonolide-微管蛋白相互作用。这也提供了进一步优化他卡内酯的靶向递送以进一步改善其抗癌功效和临床开发潜力的机会。
Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule stabilizers can limit their clinical efficacy. The taccalonolides are a unique class of microtubule stabilizers isolated from plants ofTaccathat circumvent clinically relevant mechanisms of drug resistance. Although initial reports suggested that the microtubule-stabilizing activity of the taccalonolides was independent of direct tubulin binding, additional studies have identified that potent C-22, C-23 epoxidized taccalonolides covalently bind the Aspartate 226 residue of β-tubulin and that this interaction is critical for their microtubule-stabilizing activity. The taccalonolides have distinct properties as compared to other microtubule stabilizers with regard to their biochemical effects on tubulin structure and dynamics that promote distinct cellular phenotypes. Some taccalonolides have demonstrated in vivo antitumor efficacy in drug-resistant tumor models with exquisite potency and long-lasting antitumor efficacy as a result of their irreversible target engagement. The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the taccalonolide–tubulin interaction. This also affords an opportunity to further optimize the targeted delivery of the taccalonolides to further improve their anticancer efficacy and potential for clinical development.