Crystal structure of human cyclin-dependent kinase 2 in complex with the adenine-derived inhibitor H717.

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Dreyer MK, Borcherding DR, Dumont JA, Peet NP, Tsay JT, Wright PS, Bitonti AJ, Shen J, Kim SH

Crystal structure of human cyclin-dependent kinase 2 in complex with the adenine-derived inhibitor H717.

J Med Chem. 2001 Feb 15;44(4):524-30.

PubMed ID

11170642 [ View in PubMed

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Abstract

Cyclin-dependent kinases (CDKs) are regulatory proteins of the eukaryotic cell cycle. They act after association with different cyclins, the concentrations of which vary throughout the progression of the cell cycle. As central mediators of cell growth, CDKs are potential targets for inhibitory molecules that would allow disruption of the cell cycle in order to evoke an antiproliferative effect and may therefore be useful as cancer therapeutics. We synthesized several inhibitory 2,6,9-trisubstituted purine derivatives and solved the crystal structure of one of these compounds, H717, in complex with human CDK2 at 2.6 A resolution. The orientation of the C2-p-diaminocyclohexyl portion of the inhibitor is strikingly different from those of similar moieties in other related inhibitor complexes. The N9-cyclopentyl ring fully occupies a space in the enzyme which is otherwise empty, while the C6-N-aminobenzyl substituent points out of the ATP-binding site. The structure provides a basis for the further development of more potent inhibitory drugs.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-[Trans-(4-Aminocyclohexyl)Amino]-6-(Benzyl-Amino)-9-Cyclopentylpurine	Cyclin-dependent kinase 2	IC 50 (nM)	48	7.5	30	Details