Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39
Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39
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DOI：
10.1016/j.ejca.2010.01.005
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发表时间：
2010-04-01
影响因子：
8.4
通讯作者：
Yamori, Takao
中科院分区：
文献类型：
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作者：
Kong, Dexin;Dan, Shingo;Yamori, Takao
由于越来越多的证据表明磷脂酰肌醇3-激酶（PI3K）与多种疾病特别是癌症密切相关，因此在开发PI3K抑制剂方面存在相当大的竞争。因此，新的PI3K抑制剂如ZSTK474、GDC-0941和NVP-BEZ235已经被开发出来。尽管所有这些抑制剂都被报道能抑制I类PI3K而不是几十种蛋白激酶，但它们是否有不同的分子靶点仍然未知。为了研究这种分子靶标特异性，我们通过几种新的非放射性生化试验，确定了这些新型抑制剂与经典PI3K抑制剂LY294002一起对PI3K超家族（包括I、II和III类PI3K、PI4K和PI3K相关激酶）的抑制作用。结果表明，ZSTK474和GDC-0941对PI3K超家族的抑制谱非常相似，其I类PI3K特异性远高于NVP-BEZ235和LY294002。我们进一步研究了它们对JFCR39的生长抑制作用，JFCR39是我们建立的用于分子靶标鉴定的人类癌细胞系面板，并使用COMPARE分析程序分析了它们的细胞生长抑制谱（指纹图谱）。有趣的是，我们发现ZSTK474与GDC-0941具有高度相似的指纹图谱（r = 0.863），比nlp - bez235和LY294002的指纹图谱更相似，这表明ZSTK474与GDC-0941的分子靶点比其他两种PI3K抑制剂都多，与生化检测结果一致。这些PI3K抑制剂分子靶特异性差异的生物学意义正在研究中。(C) 2010 Elsevier Ltd.版权所有。
As accumulating evidences suggest close involvement of phosphatidylinositol 3-kinase (PI3K) in various diseases particularly cancer, considerable competition occurs in development of PI3K inhibitors. Consequently, novel PI3K inhibitors such as ZSTK474, GDC-0941 and NVP-BEZ235 have been developed. Even though all these inhibitors were reported to inhibit class I PI3K but not dozens of protein kinases, whether they have different molecular targets remained unknown. To investigate such molecular target specificity, we have determined the inhibitory effects of these novel inhibitors together with classical PI3K inhibitor LY294002 on PI3K superfamily (including classes I, II, and III PI3Ks, PI4K and PI3K-related kinases) by using several novel non-radioactive biochemical assays. As a result, ZSTK474 and GDC-0941 indicated highly similar inhibition profiles for PI3K superfamily, with class I PI3K specificity much higher than NVP-BEZ235 and LY294002. We further investigated their growth inhibition effects on JFCR39, a human cancer cell line panel which we established for molecular target identification, and analysed their cell growth inhibition profiles (fingerprints) by using COMPARE analysis programme. Interestingly, we found ZSTK474 exhibited a highly similar fingerprint with GDC-0941 (r = 0.863), more similar than with that of either NVP-BEZ235 or LY294002, suggesting that ZSTK474 shares more in molecular targets with GDC-0941 than with either of the other two PI3K inhibitors, consistent with the biochemical assay result. The biological implication of the difference in molecular target specificity of these PI3K inhibitors is under investigation. (C) 2010 Elsevier Ltd. All rights reserved.