Discovery of a novel protein kinase B inhibitor by structure-based virtual screening

Protein kinase B (PKB/AKT) is a promising and attractive therapeutic target in anticancer drug development. Herein, we report the findings of virtual screening for novel ATP-competitive inhibitors of AKT-2 using 2D- and 3D-similarity searching and sequential molecular docking with two crystal structures of AKT-2. Our multistep approach led to the identification of a low micromolar AKT-2 inhibitor (IC50 = 1.5 μM) with a novel scaffold. The experimentally validated inhibitor represents the starting point for an optimization program.

Graphical abstractAn AKT-2 inhibitor with a novel scaffold was discovered by multistep virtual screening of a large commercial database.Figure optionsDownload full-size imageDownload as PowerPoint slide