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Discovery of cyclin-dependent kinase inhibitor, CR229, using structure-based drug screening

Title
Discovery of cyclin-dependent kinase inhibitor, CR229, using structure-based drug screening
Author
이철훈
Keywords
CR229; CDK inhibitor; structure-based drug screening
Issue Date
2007-10
Publisher
KOREAN SOC MICROBIOLOGY & BIOTECHNOLOGY
Citation
JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY, v. 17, No. 10, Page. 1712-1716
Abstract
To generate new scaffold candidates as highly selective and potent cyclin-dependent kinase (CDK) inhibitors, structure-based drug screening was performed utilizing 3D pharmacophore conformations of known potent inhibitors. As a result, CR229 (6-bromo-2,3,4,9-tetrahydro-carbolin-1-one) was generated as the hit-compound. A computational docking study using the X-ray crystallographic structure of CDK2 in complex with CR229 was evaluated. This predicted binding mode study of CR229 with CDK2 demonstrated that CR229 interacted effectively with the Leu83 and Glu81 residues in the ATP-binding pocket of CDK2 for the possible hydrogen bond formation. Furthermore, biochemical studies on inhibitory effects of CR229 on various kinases in the human cervical cancer HeLa cells demonstrated that CR229 was a potent inhibitor of CDK2 (IC50: 3 mu M), CDK1 (IC50: 4.9 mu M), and CDK4 (IC50: 3 9 mu M), yet had much less inhibitory effect (IC50: >20 mu M) on other kinases, such as casein kinase 2-alpha 1 (CK2-alpha 1), protein kinase A (PKA), and protein kinase C (PKC). Accordingly, these data demonstrate that CR229 is a potent CDK inhibitor with anticancer efficacy.
URI
http://kiss.kstudy.com/thesis/thesis-view.asp?key=2644691http://repository.hanyang.ac.kr/handle/20.500.11754/107000
ISSN
1017-7825; 1738-8872
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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