Discovery of Phosphatidylinositol 3-Kinase Inhibitory Compounds from the Screening Committee of Anticancer Drugs (SCADS) Library
Discovery of Phosphatidylinositol 3-Kinase Inhibitory Compounds from the Screening Committee of Anticancer Drugs (SCADS) Library
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DOI：
10.1248/bpb.33.1600
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发表时间：
2010-09-01
影响因子：
2
通讯作者：
Yamori, Takao
中科院分区：
文献类型：
--
作者：
Kong, Dexin;Yamazaki, Kanami;Yamori, Takao
已知识别现有药物的新用途是药物发现的有效方法。新型磷脂酰肌醇3-激酶（PI 3 K）抑制剂的鉴定在癌症化疗方面是重要的，因为PI 3 K与许多类型的癌症有关。为了发现新的PI 3 K抑制剂化合物，我们最近进行了抗癌药物筛选委员会（SCADS）文库的筛选，该文库主要由抗肿瘤药物和激酶抑制剂组成。结果，鉴定出六种新的PI 3 K抑制化合物，每种化合物在10 μ m时显示出超过60%的PI 3 K α抑制。黄芩素是这些抑制剂中最有效的，在1 μ m时表现出73%的抑制。黄芩素和Akt抑制剂VIII的进一步表征表明，两种化合物显示出对PI 3 K β和δ的相当的抑制，但对PI 3 K γ的活性相对较弱。还研究了Akt抑制剂VIII和黄芩素对人癌细胞系组JFCR 39的生长抑制作用，并且测定了50%细胞生长抑制所需浓度的平均对数（Log GI（50））分别为-5.59和-4.70。此外，通过使用PI 3 K抑制剂ZSTK 474作为种子，进行两种化合物与已知PI 3 K抑制剂的比较分析。我们的研究结果表明，Akt抑制剂VIII显示出与ZSTK 474相似的指纹图谱（r=0.633），而黄芩素没有（r=0.126）。这些发现表明黄芩素在细胞中的抑制特性不同于典型的PI 3 K抑制剂。
Identification of new uses for existing drugs is known to be an efficient approach in drug discovery. The identification of a novel phosphatidylinositol 3-kinase (PI3K) inhibitor is important in terms of cancer chemotherapy because PI3K is implicated in many types of cancer. In an effort to discover new PI3K inhibitory compounds, we recently carried out a screening of Screening Committee of Anticancer Drugs (SCADS) library, a compound library mainly composed of antitumor drugs and kinase inhibitors. As a result, six new PI3K inhibitory compounds were identified each of which displayed over 60% inhibition of PI3K alpha at 10 mu m. Baicalein, the most potent of these inhibitors, exhibited 73% inhibition at 1 mu m. Further characterization of Baicalein and Akt inhibitor VIII showed that both compounds displayed comparable inhibition against PI3K beta and delta, but relatively weak activity against PI3K gamma. Growth inhibition effects of Akt inhibitor VIII and Baicalein on human cancer cell line panel JFCR39 were also investigated, and the mean logarithm of the concentration required for 50% growth inhibition of cells (Log GI(50)) was determined to be -5.59 and -4.70, respectively. In addition, COMPARE analysis of the two compounds together with known PI3K inhibitors was carried out by using PI3K inhibitor ZSTK474 as a seed. Our results show that Akt inhibitor VIII displays a similar fingerprint to that of ZSTK474 (r=0.633), while Baicalein does not (r=0.126). These findings suggest the inhibition profile of Baicalein in cells is different from that of a typical PI3K inhibitor.