Discovery of MEK/PI3K dual inhibitor via structure-based virtual screening

Mitogen/extracellular signal-regulated kinase (MEK) and phosphoinositide 3-kinase (PI3K alpha) 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 IC50 values ranging from 1 to 25 mu M. One of the four newly identified MEK inhibitors was found to be also a potent inhibitor of PI3K alpha with submicromolar inhibitory activity (IC50 = 0.3 mu M). 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 PI3K alpha, 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 PI3K alpha are addressed in detail. (c) 2012 Elsevier Ltd. All rights reserved.