1KE5

CDK2 complexed with N-methyl-4-{[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

Summary for 1KE5

• Entry DOI: 10.2210/pdb1ke5/pdb
• Related: 1KE6 1KE7 1KE8 1KE9
• Descriptor: Cell division protein kinase 2, N-METHYL-4-{[(2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)METHYL]AMINO}BENZENESULFONAMIDE (3 entities in total)
• Functional Keywords: cyclin kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• Total number of polymer chains: 1
• Total formula weight: 34305.86

Authors

Bramson, H.N.,Corona, J.,Davis, S.T.,Dickerson, S.H.,Edelstein, M.,Frye, S.V.,Gampe, R.T.,Hassell, A.M.,Shewchuk, L.M.,Kuyper, L.F. (deposition date: 2001-11-14, release date: 2002-05-14, Last modification date: 2024-02-07)

Primary citation

Bramson, H.N.,Corona, J.,Davis, S.T.,Dickerson, S.H.,Edelstein, M.,Frye, S.V.,Gampe Jr., R.T.,Harris, P.A.,Hassell, A.,Holmes, W.D.,Hunter, R.N.,Lackey, K.E.,Lovejoy, B.,Luzzio, M.J.,Montana, V.,Rocque, W.J.,Rusnak, D.,Shewchuk, L.,Veal, J.M.,Walker, D.H.,Kuyper, L.F.
Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.
J.Med.Chem., 44:4339-4358, 2001

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.

PubMed: 11728181
DOI: 10.1021/jm010117d

Experimental method

X-RAY DIFFRACTION (2.2 Å)