STRUCTURAL BASIS FOR SPECIFICITY AND POTENCY OF A FLAVONOID INHIBITOROF HUMAN CDK2, A CELL-CYCLE KINASE

The central role of cyclin-dependent kinases (CDKs) in cell cycle regu lation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation, The discovery of sp ecific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds, A novel flavone, ydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochlo ride hemihydrate (L868276), is a potent inhibitor of CDKs. A chlorinat ed form, flavopiridol, is currently in phase I clinical trials as a dr ug against breast tumors, We determined the crystal structure of a com plex between CDK2 and L868276 at 2.33-Angstrom resolution and refined to an R(factor) of 20.3%. The aromatic portion of the inhibitor binds to the adenine-binding pocket of CDK2, and the position of the phenyl group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP complex structure, The analysis of the position of this phenyl ring not only explains the great differences of kinase inhibition among the flavonoid inhibitors but also explains the specificity of L868276 to inhibit CDK2 and CDC2.