title: Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.
abstract: The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation. The discovery of specific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. A novel flavone, (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl] -4H-1-benzopyran-4-one hydrochloride hemihydrate (L868276), is a potent inhibitor of CDKs. A chlorinated form, flavopiridol, is currently in phase I clinical trials as a drug against breast tumors. We determined the crystal structure of a complex between CDK2 and L868276 at 2.33 angstroms resolution and refined to an Rfactor 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.
authors.affiliation: Deartment of Chemistry, University of California, Berkeley, 94720, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: De Azevedo
authors.forename: H J
authors.initials: HJ
authors.lastname: Mueller-Dieckmann
authors.forename: U
authors.initials: U
authors.lastname: Schulze-Gahmen
authors.forename: P J
authors.initials: PJ
authors.lastname: Worland
authors.forename: E
authors.initials: E
authors.lastname: Sausville
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D002867:Chromones / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; C099022:L 868276; D010880:Piperidines; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases