Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases
Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases
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DOI：
10.1158/0008-5472.can-06-4615
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Workman, Paul
中科院分区：
文献类型：
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作者：
Raynaud, Florence I.;Eccles, Suzanne;Workman, Paul
大量证据表明，脂质磷脂酰肌苷激酶（PI3K）途径的激活参与了各种人类癌症的发生和发展。因此，PI3K抑制剂作为分子癌症治疗药物具有相当大的潜力。在这里，我们分析了一类PI3K抑制剂的一个原型的药理学特性，PI103是一种有效的抑制剂，具有低IC50值，可抑制重组PI3K亚型p110 α (2 nmol/L)、p110 β (3 nmol/L)、p110 δ (3 nmol/L)和p110 γ (15 nmol/L)。在0.5 μ mol/L浓度下，PI103对TORC1的抑制率为83.9%，对DNA-PK的IC50为14 nmol/L。在一组70个蛋白激酶中，PI103缺乏活性显示了对PI3K家族的高度选择性。PI103在体外有效抑制多种人类癌细胞的增殖和侵袭，并显示出与PI3K信号抑制一致的生物标志物调节。PI103被广泛代谢，但迅速分布到组织和肿瘤。这导致了8种不同的PI3K通路异常的人类肿瘤异种移植模型的肿瘤生长延迟。在U87MG胶质瘤中，AKT磷酸化水平下降，与药物水平一致。我们还在原位乳腺癌和卵巢癌异种移植模型中发现了抑制侵袭的作用，并获得了PI103具有抗血管生成潜力的证据。尽管PI103在体内代谢迅速，但它是探索I类PI3K生物学功能的有价值的工具化合物，并且重要地代表了进一步优化这类新型靶向分子癌症治疗的先导。
Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we deta the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110 alpha (2 nmol/L), p110 beta (3 nmol/L), p110 delta (3 nmol/L), and p110 gamma (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 mu mol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic.