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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-{Angstrom} resolution and refined to an R{sub 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. 36 refs., 4 figs., 2 tabs.

Authors:
; ;  [1]
  1. Lawrence Berkeley National Lab., CA (United States) [and others
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
258594
DOE Contract Number:
AC03-76SF00098
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; Journal Volume: 93; Journal Issue: 7; Other Information: PBD: 2 Apr 1996
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; FLAVONES; STRUCTURE-ACTIVITY RELATIONSHIPS; PHOSPHOTRANSFERASES; SPECIFICITY

Citation Formats

Filgueira de Azevedo, W. Jr., Mueller-Dieckmann, H.J., and Schulze-Gahmen, U. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. United States: N. p., 1996. Web. doi:10.1073/pnas.93.7.2735.
Filgueira de Azevedo, W. Jr., Mueller-Dieckmann, H.J., & Schulze-Gahmen, U. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. United States. doi:10.1073/pnas.93.7.2735.
Filgueira de Azevedo, W. Jr., Mueller-Dieckmann, H.J., and Schulze-Gahmen, U. 1996. "Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase". United States. doi:10.1073/pnas.93.7.2735.
@article{osti_258594,
title = {Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase},
author = {Filgueira de Azevedo, W. Jr. and Mueller-Dieckmann, H.J. and Schulze-Gahmen, U.},
abstractNote = {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-{Angstrom} resolution and refined to an R{sub 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. 36 refs., 4 figs., 2 tabs.},
doi = {10.1073/pnas.93.7.2735},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 7,
volume = 93,
place = {United States},
year = 1996,
month = 4
}
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