WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant
WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant
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WJD008 是一种双重磷脂酰肌醇 3 激酶 (PI3K)/雷帕霉素抑制剂的哺乳动物靶标，可防止 PI3K 信号传导并抑制具有致癌 PI3K 突变体的转化细胞的增殖
DOI：
10.1124/jpet.110.167940
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Ding, Jian
中科院分区：
文献类型：
--
作者：
Li, Ting;Wang, Jia;Ding, Jian
磷脂酰肌醇-3-激酶（PI 3 K）-蛋白激酶B（Akt）-哺乳动物雷帕霉素靶蛋白（mTOR）信号传导途径通常在各种人类癌症中被组成性激活，从而为癌症治疗提供了经验证的靶标。在基于PI 3 K靶点设计和合成的一系列5-氰基-6-吗啉代-4-取代嘧啶类似物中，选择4-（2-（二甲氨基）乙烯基）-2-（3-羟基苯基）-6-吗啉代嘧啶-5-甲腈（WJD 008）进行进一步药理学表征，因为其对PI 3 K信号传导的有效活性。WJD 008抑制PI 3 K α和mTOR的激酶活性，对PIKK家族成员的活性较低。在细胞环境中，WJD 008消除了胰岛素样生长因子-I-激活的PI 3 K-Akt-mTOR信号级联，并阻断了含有增强的绿色荧光蛋白-磷酸肌醇的一般受体、同种型1-普列克底物蛋白同源融合蛋白的普列克底物蛋白同源结构域的膜易位，表明下调了磷脂酰肌醇（3，4，WJD 008诱导的5）-三磷酸输出导致PI 3 K途径失活。因此，WJD 008将细胞阻滞在G1期而不诱导凋亡。此外，WJD 008逆转了由p110α H1047 R致癌突变引起的PI 3 K通路的过度激活，并抑制了携带该突变体的转化RK 3E细胞的增殖和克隆形成。WJD 008上级pan-PI 3 K抑制剂渥曼青霉素对抗一组癌细胞的增殖，而与它们的PI 3 K通路状态或组织起源无关。综上所述，WJD 008是一种有效的PI 3 K/mTOR双重调节剂，在肿瘤细胞和PIK 3CA突变的转化细胞中具有抗增殖和抗克隆形成活性，这为设计和开发这种化学支架作为抗癌药物提供了新的线索。
The phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway is often constitutively activated in various human cancers, providing validated targets for cancer therapy. Among a series of 5-cyano-6-morpholino-4-substituted-pyrimidine analogs designed and synthesized based on PI3K target, 4-(2-(dimethylamino)vinyl)-2-(3-hydroxyphenyl)-6-morpholinopyrimidine-5-carbonitrile (WJD008) was selected for further pharmacological characterization because of its potent activity against PI3K signaling. WJD008 inhibited kinase activity of PI3Kα and mTOR with less activity against PIKK family members. In cellular settings, WJD008 abrogated insulin-like growth factor-I-activated PI3K-Akt-mTOR signaling cascade and blocked the membrane translocation of a pleckstrin homology domain containing enhanced green fluorescent protein-general receptor for phosphoinositides, isoform 1-pleckstrin homology fusion protein, suggesting down-regulation of phosphatidylinositol (3,4,5)-trisphosphate output induced by WJD008 resulted in inactivation of PI3K pathway. Consequently, WJD008 arrested cells in G1 phase without induction of apoptosis. Furthermore, WJD008 reversed the hyperactivation of the PI3K pathway caused by the oncogenic mutation of p110α H1047R and suppressed the proliferation and clonogenesis of transformed RK3E cells harboring this mutant. WJD008 was superior to the pan-PI3K inhibitor wortmannin against proliferation of a panel of cancer cells independently of their status of PI3K pathway or tissue originations. In summary, WJD008 is a potent dual PI3K/mTOR modulator with antiproliferative and anticlonogenic activity in tumor cells and transformed cells with PIK3CA mutant, which provides new clues for the design and development of this chemical scaffold as an anticancer drug.