A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.
A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.
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聚乙二醇化 TC11 是一种新型苯基邻苯二甲酰亚胺衍生物，可改善药代动力学特性，并通过 G2/M 细胞周期阻滞诱导高危骨髓瘤细胞凋亡。
DOI：
10.1016/j.bbrc.2017.08.159
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hattori Y
中科院分区：
文献类型：
--
作者：
Aida S;Hozumi M;Ichikawa D;Iida K;Yonemura Y;Tabata N;Yamada T;Matsushita M;Sugai T;Yanagawa H;Hattori Y
尽管多发性骨髓瘤（MM）新药的开发，MM患者的预后与高风险的细胞遗传学异常，如t（4; 14）和del 17 p仍然很差。我们报道了一种新型的苯基邻苯二甲酰亚胺衍生物TC 11在体外和体内诱导MM细胞凋亡，并且TC 11直接与α-微管蛋白和核磷蛋白1（NPM 1）结合。然而，TC 11显示出低的水溶性和差的药代动力学特性。在这里，我们合成了一种水溶性的TC 11衍生物，PEG（E）-TC 11，其中HOEtO-TC 11与PEG通过酯键聚乙二醇化，我们检查了其抗骨髓瘤活性。我们观察到PEG（E）-TC 11及其水解产物HOEtO-TC 11诱导MM细胞G2/M期阻滞和凋亡。将PEG（E）-TC 11腹腔注射到异种移植小鼠中显示出改善的药代动力学特性和显著延迟的肿瘤生长。TC 11及其衍生物不与cereblon（CRBN）结合，而cereblon是沙利度胺诱导致畸性的负责分子。这些结果表明PEG（E）-TC 11是治疗高危MM的良好候选药物。
Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cellsin vitroandin vivo, and TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM.