Institut de Chimie des Milieux et des Matériaux de Poitiers (IC2MP), Université de Poitiers, CNRS, Groupe "Systèmes Moléculaires Programmés", 4 rue Michel Brunet, TSA 51106, F-86073, Poitiers, France.
ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, 29680, Roscoff, France.
Eur J Med Chem. 2018 Oct 5;158:1-6. doi: 10.1016/j.ejmech.2018.08.100. Epub 2018 Sep 3.
We report on the synthesis and in vitro biological evaluations of a nanomolar protein kinase inhibitor (PKI) and its β-glucuronidase-responsive albumin-binding prodrug. The highly potent PKI is 400-3400 times more cytotoxic than the well-known PKI Roscovitine. The prodrug is able to bind covalently to human serum albumin through Michael addition and release the cytotoxic PKI in the presence of β-glucuronidase, an enzyme over-expressed in the microenvironment of solid tumours.
我们报告了一种纳摩尔级蛋白激酶抑制剂（PKI）及其β-葡糖苷酸酶响应型白蛋白结合前药的合成和体外生物学评价。该高活性 PKI 的细胞毒性比著名的 PKI Roscovitine 高 400-3400 倍。该前药能够通过迈克尔加成与人血清白蛋白共价结合，并在β-葡糖苷酸酶存在下释放具有细胞毒性的 PKI，β-葡糖苷酸酶在实体瘤微环境中过度表达。
