Wu Shuhong, Wang Li, Huang Xiao, Cao Mengru, Hu Jing, Li Hongyu, Zhang Hui, Sun Xiaoping, Meng Qing H, Hofstetter Wayne L, Roth Jack A, Swisher Stephen G, Fang Bingliang
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bioorg Med Chem. 2014 Oct 1;22(19):5234-40. doi: 10.1016/j.bmc.2014.08.006. Epub 2014 Aug 14.
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 (150-300 mg/kg, ip) 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.
通过对携带和不携带致癌KRAS基因的同基因细胞系进行合成致死筛选，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（癌抑素-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容易形成二聚体，这大大降低了其抗癌活性。为了改善NSC-743380的理化性质，我们用环己基乙酸修饰NSC-743380，合成了一种NSC-743380的前药，命名为癌抑素-266，并评估了其体外和体内性质。癌抑素-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。在小鼠体内给予癌抑素-266导致NSC-743380的释放，这改善了NSC-743380的药代动力学。组织分布分析显示，癌抑素-266沉积在肝脏中，而释放的NSC-743380在肝脏、肺、肾脏和皮下肿瘤中被检测到。在较高剂量水平治疗（150 - 300 mg/kg，腹腔注射）下，癌抑素-266在小鼠中的耐受性比母体药物更好，这表明前药降低了母体药物的急性毒性。我们的结果表明，前药策略可以改善NSC-743380的稳定性、药代动力学性质和安全性。
