文章基本信息

标题：Discovery of Phosphatidylinositol 3-Kinase Inhibitory Compounds from the Screening Committee of Anticancer Drugs (SCADS) Library
本地全文：下载
作者：Dexin Kong ; Kanami Yamazaki ; Takao Yamori 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2010
卷号：33
期号：9
页码：1600-1604
DOI：10.1248/bpb.33.1600
出版社：The Pharmaceutical Society of Japan
摘要：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 PI3Kα at 10 μ M . Baicalein, the most potent of these inhibitors, exhibited 73% inhibition at 1 μ M . Further characterization of Baicalein and Akt inhibitor VIII showed that both compounds displayed comparable inhibition against PI3Kβ and δ, but relatively weak activity against PI3Kγ. 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 GI₅₀) 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.
关键词：phosphatidylinositol 3-kinase inhibitor;compound library;Baicalein;drug discovery;COMPARE analysis