Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Biol Pharm Bull. 2010;33(9):1600-4. doi: 10.1248/bpb.33.1600.
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 PI3Kalpha at 10 microM. Baicalein, the most potent of these inhibitors, exhibited 73% inhibition at 1 microM. Further characterization of Baicalein and Akt inhibitor VIII showed that both compounds displayed comparable inhibition against PI3Kbeta and delta, but relatively weak activity against PI3Kgamma. 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.
已有研究表明，对现有药物进行新用途的鉴定是药物研发中一种非常有效的方法。在癌症化疗方面，鉴定新型的磷脂酰肌醇 3-激酶（PI3K）抑制剂非常重要，因为 PI3K 与多种类型的癌症有关。为了发现新的 PI3K 抑制化合物，我们最近对抗癌药物筛选委员会（SCADS）化合物库进行了筛选，该化合物库主要由抗肿瘤药物和激酶抑制剂组成。结果，我们鉴定出了六种新的 PI3K 抑制化合物，它们在 10μM 时对 PI3Kalpha 的抑制率均超过 60%。其中最有效的化合物黄芩素，在 1μM 时抑制率达到 73%。进一步对黄芩素和 Akt 抑制剂 VIII 的特性进行了研究，结果表明这两种化合物对 PI3Kbeta 和 delta 的抑制作用相当，但对 PI3Kgamma 的活性较弱。还研究了 Akt 抑制剂 VIII 和黄芩素对人癌细胞系 JFCR39 panel 的生长抑制作用，确定细胞 50%生长抑制所需的浓度的对数值（Log GI50）分别为-5.59 和-4.70。此外，还通过使用 PI3K 抑制剂 ZSTK474 作为种子，对两种化合物与已知 PI3K 抑制剂进行了 COMPARE 分析。结果表明，Akt 抑制剂 VIII 的指纹图谱与 ZSTK474 相似（r=0.633），而黄芩素则不然（r=0.126）。这些发现表明，黄芩素在细胞中的抑制谱与典型的 PI3K 抑制剂不同。
