Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
复制标题
DOI：
10.1158/1535-7163.mct-08-0017
复制
发表时间：
2008-07-01
影响因子：
5.7
通讯作者：
Garcia-Echeverria, Carlos
中科院分区：
文献类型：
--
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
磷脂酰肌醇3-激酶（PI3K）/AKT/哺乳动物雷帕霉素抑制剂（MTOR）途径通常在人类肿瘤细胞中组成式激活，为抗癌治疗疗法提供独特的机会。 NVP-BEZ235是一种Imidazo [4,5-C]喹啉衍生物，通过与这些酶的ATP结合裂解结合来抑制PI3K和MTOR激酶活性。在使用人肿瘤细胞系的细胞环境中，该分子能够有效，特异性地阻断PI3K途径的功能障碍激活，从而诱导G，停滞。 NVP-BEZ235的细胞活性在人体癌的体内模型中很好地翻译出来。因此，该化合物的耐受性良好，口服施用时显示出疾病的停滞，并在体内组合研究中使用时增强了其他抗癌药的功效。对肿瘤组织的体内药代动力学/药效学分析显示，化合物浓度与PI3K/AKT途径抑制之间存在时间依赖性相关性。总体而言，临床前数据表明，NVP-BEZ235是具有良好药物特性的有效双PI3K/MTOR调制器。 NVP-BEZ235目前正在I期临床试验中。
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G, arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.