A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma
A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma
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DOI：
10.1016/j.ccr.2006.03.029
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发表时间：
2006-05-01
期刊：
影响因子：
50.3
通讯作者：
Weiss, William A.
中科院分区：
文献类型：
--
作者：
Fan, Qi-Wen;Knight, Zachary A.;Weiss, William A.
脂质激酶的P13激酶家族通过产生第二信使磷脂酰肌醇-3，4，5-三磷酸来促进细胞生长和存活。为了确定由P13激酶激活驱动的癌症的关键靶点，我们筛选了一组靶向该酶家族的有效且结构多样的药物样分子。令人惊讶的是，单一药剂（PI-103）在神经胶质瘤细胞中实现增殖停滞，尽管许多化合物能够通过其下游效应物Akt阻断P13激酶信号传导。PI-103独特的细胞活性直接追溯到其抑制P13激酶α和mTOR的能力。PI-103在异种移植肿瘤中显示出显著的活性，没有可观察到的毒性。这些数据证明了由于mTOR和P13激酶α在恶性胶质瘤中的组合抑制而产生的疗效。
The P13 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidy-linositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of P13 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block P13 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both P13 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and P13 kinase alpha in malignant glioma.