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

Article Details

Citation

Bramson HN, Corona J, Davis ST, Dickerson SH, Edelstein M, Frye SV, Gampe RT Jr, Harris PA, Hassell A, Holmes WD, Hunter RN, Lackey KE, Lovejoy B, Luzzio MJ, Montana V, Rocque WJ, Rusnak D, Shewchuk L, Veal JM, Walker DH, Kuyper LF

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

J Med Chem. 2001 Dec 6;44(25):4339-58.

PubMed ID
11728181 [ View in PubMed
]
Abstract

Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-{[(2,2-dioxido-1,3-dihydro-2-benzothien-5-yl)amino]methylene}-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-oneCyclin-dependent kinase 2IC 50 (nM)8.97.522Details
3-{[4-([amino(imino)methyl]aminosulfonyl)anilino]methylene}-2-oxo-2,3-dihydro-1H-indoleCyclin-dependent kinase 2IC 50 (nM)6607.522Details
4-{[(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-N-(1,3-thiazol-2-yl)benzenesulfonamideCyclin-dependent kinase 2IC 50 (nM)10007.522Details
N-methyl-{4-[2-(7-oxo-6,7-dihydro-8H-[1,3]thiazolo[5,4-e]indol-8-ylidene)hydrazino]phenyl}methanesulfonamideCyclin-dependent kinase 2IC 50 (nM)5.77.522Details
N-Methyl-4-{[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamideCyclin-dependent kinase 2IC 50 (nM)5607.522Details