Fan Qi-Wen, Knight Zachary A, Goldenberg David D, Yu Wei, Mostov Keith E, Stokoe David, Shokat Kevan M, Weiss William A
Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.
Cancer Cell. 2006 May;9(5):341-9. doi: 10.1016/j.ccr.2006.03.029.
The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 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 PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 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 PI3 kinase alpha in malignant glioma.
脂质激酶的PI3激酶家族通过生成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PI3激酶激活驱动的癌症的关键靶点,我们筛选了一组针对该酶家族的强效且结构多样的类药物分子。令人惊讶的是,尽管许多化合物能够通过其下游效应器Akt阻断PI3激酶信号传导,但单一药物(PI-103)却能使胶质瘤细胞发生增殖停滞。PI-103独特的细胞活性直接归因于其抑制PI3激酶α和mTOR的能力。PI-103在异种移植肿瘤中显示出显著活性,且无明显毒性。这些数据表明,在恶性胶质瘤中,mTOR和PI3激酶α的联合抑制具有新出现的疗效。