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. doi: 10.1021/jm010117d.
H N Bramson  1 ,  J Corona ,  S T Davis ,  S H Dickerson ,  M Edelstein ,  S V Frye ,  R T Gampe Jr ,  P A Harris ,  A Hassell ,  W D Holmes ,  R N Hunter ,  K E Lackey ,  B Lovejoy ,  M J Luzzio ,  V Montana ,  W J Rocque ,  D Rusnak ,  L Shewchuk ,  J M Veal ,  D H Walker ,  L F Kuyper
Affiliations
  • 1. GlaxoSmithKline Inc., Five Moore Drive, Research Triangle Park, North Carolina 27709, USA.
PMID: 11728181 DOI: 10.1021/jm010117d
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.

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