Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380.
Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380.
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DOI：
10.1016/j.bmc.2014.08.006
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发表时间：
2014-10-01
影响因子：
3.5
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Wu S;Wang L;Huang X;Cao M;Hu J;Li H;Zhang H;Sun X;Meng QH;Hofstetter WL;Roth JA;Swisher SG;Fang B
通过对具有和不具有致癌 KRAS 基因的同基因细胞系进行合成致死性筛选，并通过先导化合物优化，我们最近开发了一种新型抗癌剂，命名为 NSC-743380 (oncrasin-72)，它在包括 KRAS 突变癌细胞在内的一部分癌细胞系中具有良好的体外和体内抗癌活性。然而，NSC-743380 往往会形成二聚体，从而大大降低其抗癌活性。为了改善NSC-743380的理化性质，我们通过用环己基乙酸修饰NSC-743380来合成NSC-743380的前药，命名为oncrasin-266，并评估其体外和体内性质。 Oncrasin-266 在磷酸盐缓冲盐水中以时间依赖性方式自发水解，并且在粉末或储备溶液中比 NSC-743380 更稳定。在小鼠体内给予 oncrasin-266 会导致 NSC-743380 的释放，从而改善 NSC-743380 的药代动力学。组织分布分析显示，Oncrasin-266 沉积在肝脏中，而释放的 NSC-743380 在肝脏、肺、肾和皮下肿瘤中检测到。 Oncrasin-266 在较高剂量水平治疗（150-300mg/kg，腹腔注射）下在小鼠中比母体药物具有更好的耐受性，表明前药降低了母体药物的急性毒性。我们的结果表明，前药策略可以提高 NSC-743380 的稳定性、药代动力学特性和安全性。
Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300mg/kg, i.p.) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380.
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