In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.
In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.
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DOI：
10.3390/molecules27134244
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发表时间：
2022-07-01
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影响因子：
--
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微管稳定剂（MSA）是用于治疗三阴性乳腺癌（TNBC）的一类化合物，三阴性乳腺癌是乳腺癌的一种亚型，其中化疗仍然是患者的护理标准。紫杉烷类如紫杉醇和多西他赛已在临床上证明了对TNBC的功效，然而由于患者中紫杉烷耐药性的上升，需要鉴定新类别的MSA。（−）-赞潘生丁是一种共价微管稳定剂，可以在体外避免紫杉烷耐药性，但尚未评估体内抗肿瘤疗效。在这里，我们确定（-）-扎潘鲁肽在TNBC细胞系中具有与紫杉醇相似的效力和功效，但由于其共价结合而显著更持久。我们还提供了第一个报告的体内抗肿瘤评价（-）-赞潘生丁，我们确定它具有有效和持久的抗肿瘤疗效时，提供瘤内。未来对赞潘内酯的研究将进一步评估其药效团并确定改善其全身治疗窗口的方法，这将使该化合物通过其规避紫杉烷耐药机制的能力而成为临床开发的潜在候选药物。
Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (−)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (−)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (−)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.
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影响因子：
2.7
作者：
Chen G;Gonzalez M;Jiang Z;Zhang Q;Wang G;Chen QH
通讯作者：
Chen QH
影响因子：
4.1
作者：
Morris JD;Takahashi-Ruiz L;Persi LN;Summers JC;McCauley EP;Chan PYW;Amberchan G;Lizama-Chamu I;Coppage DA;Crews P;Risinger AL;Johnson TA
通讯作者：
Johnson TA
影响因子：
14.8
作者：
Buey, Ruben M.;Calvo, Enrique;Diaz, J. Fernando
通讯作者：
Diaz, J. Fernando
影响因子：
4.2
作者：
Johnson, Tyler A.;Morris, Joseph D.;Crews, Phillip
通讯作者：
Crews, Phillip
影响因子：
3.5
作者：
Sanchez-Murcia, Pedro A.;Mills, Alberto;Gago, Federico
通讯作者：
Gago, Federico