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Title: Toward understanding the structural basis of cyclin-dependentkinase 6 specific inhibition

Abstract

CDKs are key players in cell cycle control, and genetic alterations of CDKs and their regulators have been linked to a variety of cancers. Hence, CDKs are obvious targets for therapeutic intervention in various proliferative diseases, including cancer. To date, drug design efforts have mostly focused on CDK2 because methods for crystallization of its inhibitor complexes have been well established. CDK4 and CDK6, however, may be at least as important enzymes for cell cycle regulation and could provide alternative treatment options. We describe here two complex structures of human CDK6 with a very specific kinase inhibitor, PD0332991, which is based on a pyrido[2,3-d]pyrimidin-7-one scaffold, and with the less specific aminopurvalanol inhibitor. Analysis of the structures suggests that relatively small conformational differences between CDK2 and CDK6 in the hinge region are contributing to responsible for the inhibitor specificity by inducing changes in the inhibitor orientation that lead to sterical clashes in CDK2 but not CDK6. These complex structures provide valuable insights for the future development of CDK specific inhibitors.

Authors:
;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director, Office of Science; National Institutes ofHealth
OSTI Identifier:
887205
Report Number(s):
LBNL-60698
Journal ID: ISSN 0022-2623; JMCMAR; R&D Project: 8712; TRN: US200617%%604
DOE Contract Number:  
DE-AC02-05CH11231; NIH8712
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 49; Related Information: Journal Publication Date: 05/28/2006
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CELL CYCLE; CRYSTALLIZATION; DESIGN; DISEASES; ENZYMES; GENETICS; NEOPLASMS; ORIENTATION; PHOSPHOTRANSFERASES; REGULATIONS; SPECIFICITY; TARGETS; cyclin-dependent kinase 6 kinase inhibitors cell cycle crystalstructure

Citation Formats

Lu, Heshu, and Schulze-Gahmen, Ursula. Toward understanding the structural basis of cyclin-dependentkinase 6 specific inhibition. United States: N. p., 2006. Web. doi:10.1021/jm0600388.
Lu, Heshu, & Schulze-Gahmen, Ursula. Toward understanding the structural basis of cyclin-dependentkinase 6 specific inhibition. United States. doi:10.1021/jm0600388.
Lu, Heshu, and Schulze-Gahmen, Ursula. Thu . "Toward understanding the structural basis of cyclin-dependentkinase 6 specific inhibition". United States. doi:10.1021/jm0600388.
@article{osti_887205,
title = {Toward understanding the structural basis of cyclin-dependentkinase 6 specific inhibition},
author = {Lu, Heshu and Schulze-Gahmen, Ursula},
abstractNote = {CDKs are key players in cell cycle control, and genetic alterations of CDKs and their regulators have been linked to a variety of cancers. Hence, CDKs are obvious targets for therapeutic intervention in various proliferative diseases, including cancer. To date, drug design efforts have mostly focused on CDK2 because methods for crystallization of its inhibitor complexes have been well established. CDK4 and CDK6, however, may be at least as important enzymes for cell cycle regulation and could provide alternative treatment options. We describe here two complex structures of human CDK6 with a very specific kinase inhibitor, PD0332991, which is based on a pyrido[2,3-d]pyrimidin-7-one scaffold, and with the less specific aminopurvalanol inhibitor. Analysis of the structures suggests that relatively small conformational differences between CDK2 and CDK6 in the hinge region are contributing to responsible for the inhibitor specificity by inducing changes in the inhibitor orientation that lead to sterical clashes in CDK2 but not CDK6. These complex structures provide valuable insights for the future development of CDK specific inhibitors.},
doi = {10.1021/jm0600388},
journal = {Journal of Medicinal Chemistry},
number = ,
volume = 49,
place = {United States},
year = {Thu Jan 12 00:00:00 EST 2006},
month = {Thu Jan 12 00:00:00 EST 2006}
}