Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Floyd Curl Drive, 78229, San Antonio, TX, USA.
Department of Chemistry and Biochemistry and Institute for Natural Products Applications and Research Technologies, The University of Oklahoma, 101 Stephenson Parkway, 73019, Norman, OK, USA.
Prog Chem Org Nat Prod. 2020;112:183-206. doi: 10.1007/978-3-030-52966-6_3.
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 of Tacca that 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.
微管稳定剂是治疗许多实体瘤的主要药物，并且在与分子靶向抗癌药物和免疫疗法联合治疗中继续发挥作用。然而，对微管稳定剂的先天和获得性耐药性会限制其临床疗效。塔卡醇类化合物是从塔卡植物中分离出的一类独特的微管稳定剂，可以规避与临床相关的耐药机制。尽管最初的报告表明，塔卡醇类化合物的微管稳定活性不依赖于直接结合微管蛋白，但进一步的研究表明，有效的 C-22、C-23 环氧化塔卡醇类化合物与β-微管蛋白的天冬氨酸 226 残基共价结合，这种相互作用对于它们的微管稳定活性至关重要。与其他微管稳定剂相比，塔卡醇类化合物具有独特的性质，它们对微管蛋白结构和动力学的生化作用促进了不同的细胞表型。一些塔卡醇类化合物在耐药性肿瘤模型中表现出体内抗肿瘤疗效，具有极高的效力和持久的抗肿瘤疗效，这是由于它们的不可逆靶标结合。最近确定了塔卡醇骨架上一个可修饰的位点，这为塔卡醇-微管蛋白相互作用的特异性提供了证据。这也为进一步优化塔卡醇类化合物的靶向递送提供了机会，以进一步提高其抗癌疗效和临床开发潜力。
