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

De Azevedo WF Jr,Mueller-Dieckmann HJ,Schulze-Gahmen U,Worland PJ,Sausville E,Kim SH

doi

10.1073/pnas.93.7.2735

subject

Has Abstract

pub_date

1996-04-02 00:00:00

pages

2735-40

issue

7

eissn

0027-8424

issn

1091-6490

journal_volume

93

pub_type

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