Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
Bioorg Med Chem Lett. 2012 Aug 1;22(15):4946-50. doi: 10.1016/j.bmcl.2012.06.041. Epub 2012 Jun 21.
Mitogen/extracellular signal-regulated kinase (MEK) and phosphoinositide 3-kinase (PI3Kα) are considered to be promising targets for the development of anticancer therapeutics. We report the first example of the successful application of structure-based virtual screening to identify novel inhibitors of MEK with IC(50) values ranging from 1 to 25 μM. One of the four newly identified MEK inhibitors was found to be also a potent inhibitor of PI3Kα with submicromolar inhibitory activity (IC(50)=0.3 μM). Because this dual inhibitor was screened for having desirable physicochemical properties as a drug candidate as well as the high inhibitory activities against MEK and PI3Kα, it warrants further development through structure-activity relationship (SAR) studies to optimize the inhibitory and anticancer activities. Structural features relevant to the stabilization of the dual inhibitor in the ATP-binding sites of MEK1 and PI3Kα are addressed in detail.
丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK）和磷酸肌醇 3-激酶（PI3Kα）被认为是开发抗癌治疗药物的有前途的靶点。我们报告了首例成功应用基于结构的虚拟筛选来鉴定新型 MEK 抑制剂的实例，这些抑制剂的 IC（50）值范围为 1 至 25 μM。新鉴定的四个 MEK 抑制剂之一被发现也是 PI3Kα 的有效抑制剂，具有亚微摩尔抑制活性（IC（50）=0.3 μM）。由于该双重抑制剂被筛选出具有作为候选药物的理想理化性质以及对 MEK 和 PI3Kα 的高抑制活性，因此值得通过结构活性关系（SAR）研究进一步开发以优化抑制和抗癌活性。详细讨论了与双重抑制剂在 MEK1 和 PI3Kα 的 ATP 结合位点中稳定相关的结构特征。
