Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): Design, synthesis, enzymatic activities, and X-ray crystallographic analysis

Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dion e 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initia l lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydr o-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of th e lead compound bound to CDK2 provided the basis for analogue design. A sem iautomated method of ligand docking was used to select compounds for synthe sis, and a number of compounds with low nanomolar inhibitory activity versu s CDK2 were identified. Enzyme binding determinants for several analogues w ere evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency similar to 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.