TAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. In vitro, TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in normal lung diploid fibroblast cell lines WI-38 and MRC5. In vivo, TAS-119 enhanced the antitumor efficacy of paclitaxel and docetaxel in multiple models at doses inhibitory to Aurora A in tumors. Moreover, the drug combination was well tolerated, and TAS-119 did not exaggerate clinically documented side effects of taxanes, neutropenia and neurotoxicity, in rats. The same TAS-119 concentration enhanced the cell growth inhibitory activity of three clinically approved taxanes, paclitaxel, docetaxel, and cabazitaxel. The degree of enhancement calculated as fold of change of the IC50 value for each taxane was almost the same among the three taxanes. We conducted in vitro and in vivo experiments to develop an optimized combination therapy regimen for TAS-119 with paclitaxel/docetaxel. Using in vitro and in vivo models, we tested the drug administration order for TAS-119 combined with paclitaxel and the TAS-119 treatment duration. The best regimen in preclinical models was combining paclitaxel or docetaxel treatment with 4 days of TAS-119 dosing, which was initiated on the same day as the paclitaxel or docetaxel administration or one day later. This information provided guidance for the design of a clinical trial of TAS-119 and paclitaxel or docetaxel combination.

中文翻译：

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Aurora A 抑制剂 TAS-119 增强紫杉烷类的体外和体内抗肿瘤功效：临床前研究作为临床开发和试验设计的指导

TAS-119 是一种新型的口服活性选择性极光激酶 A 抑制剂，被确定为与紫杉烷类药物联合进行疗效测试的临床候选药物。在体外，TAS-119 增强了来自各种组织的多种人类癌细胞系中紫杉醇的细胞生长抑制，包括紫杉醇抗性细胞系。有趣的是，TAS-119 没有增强正常肺二倍体成纤维细胞系 WI-38 和 MRC5 中紫杉醇的抗肿瘤活性。在体内，TAS-119 在多种模型中增强了紫杉醇和多西紫杉醇的抗肿瘤功效，剂量可抑制肿瘤中的 Aurora A。此外，该药物组合具有良好的耐受性，并且 TAS-119 没有夸大临床记录的紫杉烷类副作用、中性粒细胞减少症和大鼠神经毒性。相同的 TAS-119 浓度增强了三种临床批准的紫杉烷、紫杉醇、多西紫杉醇和卡巴他赛的细胞生长抑制活性。以每种紫杉烷的 IC50 值变化倍数计算的增强程度在三种紫杉烷中几乎相同。我们进行了体外和体内实验，以开发 TAS-119 与紫杉醇/多西他赛的优化联合治疗方案。使用体外和体内模型，我们测试了 TAS-119 联合紫杉醇的给药顺序和 TAS-119 治疗持续时间。临床前模型中的最佳方案是将紫杉醇或多西紫杉醇治疗与 4 天的 TAS-119 给药相结合，该给药在紫杉醇或多西紫杉醇给药的同一天或一天​​后开始。