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

被引：253

作者：

Bramson, HN ^{[1
]}

Corona, J ^{[1
]}

Davis, ST ^{[1
]}

Dickerson, SH ^{[1
]}

Edelstein, M ^{[1
]}

Frye, SV ^{[1
]}

Gampe, RT ^{[1
]}

Harris, PA ^{[1
]}

Hassell, A ^{[1
]}

Holmes, WD ^{[1
]}

Hunter, RN ^{[1
]}

Lackey, KE ^{[1
]}

Lovejoy, B ^{[1
]}

Luzzio, MJ ^{[1
]}

Montana, V ^{[1
]}

Rocque, WJ ^{[1
]}

Rusnak, D ^{[1
]}

Shewchuk, L ^{[1
]}

Veal, JM ^{[1
]}

Walker, DH ^{[1
]}

Kuyper, LF ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 25期

关键词：

D O I：

10.1021/jm010117d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 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.

引用

页码：4339 / 4358

页数：20

共 60 条

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