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

Cyclin-dependent kinases (CDKs) are regulatory proteins of the eukaryotic c ell cycle. They act after association with different cyclins, the concentra tions of which vary throughout the progression of the cell cycle. As centra l mediators of cell growth, CDKs are potential targets for inhibitory molec ules that would allow disruption of the cell cycle in order to evoke an ant iproliferative effect and may therefore be useful as cancer therapeutics. W e synthesized several inhibitory 2,6,9-trisubstituted purine derivatives an d solved the crystal structure of one of these compounds, H717, in complex with human CDK2 at 2.6 Angstrom resolution. The orientation of the C-2-p-di aminocyclohexyl portion of the inhibitor is strikingly different from those of similar moieties in other related inhibitor complexes. The N-9-cyclopen tyl ring fully occupies a space in the enzyme which is otherwise empty, whi le the C-6-N-aminobenzyl substituent points out of the ATP-binding site. Th e structure provides a basis for the further development of more potent inh ibitory drugs.