Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review
-
Published:2019-05-09
Issue:7
Volume:20
Page:716-726
-
ISSN:1389-4501
-
Container-title:Current Drug Targets
-
language:en
-
Short-container-title:CDT
Author:
Volkart Priscylla Andrade1, Bitencourt-Ferreira Gabriela1, Souto André Arigony1, de Azevedo Walter Filgueira1
Affiliation:
1. School of Sciences - Pontifical Catholic University of Rio Grande do Sul (PUCRS). Av. Ipiranga, 6681 Porto Alegre/RS 90619-900, Brazil
Abstract
<P>Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the
cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular
basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with
functional studies.
</P><P>
Objective: Our goal here is to review recent functional and structural studies directed to understanding
the role of CDK2 in cancer and senescence.
</P><P>
Methods: There are over four hundreds of crystallographic structures available for CDK2, many of
them with binding affinity information. We use this abundance of data to analyze the essential features
responsible for the inhibition of CDK2 and its function in cancer and senescence.
</P><P>
Results: The structural and affinity data available CDK2 makes it possible to have a clear view of the
vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis
for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the
relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the
participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural
and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence.
</P><P>
Conclusion: Here, we analyzed structural information for CDK2 in combination with inhibitors and
mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding
affinity data were available. From this analysis, we identified the significant intermolecular
interactions responsible for binding affinity. This knowledge may guide the future development of
CDK2 inhibitors targeting cancer and cellular senescence.</P>
Funder
National Council for Scientific and Technological Development
Publisher
Bentham Science Publishers Ltd.
Subject
Clinical Biochemistry,Drug Discovery,Pharmacology,Molecular Medicine
Reference95 articles.
1. Sausville EA, Johnson J, Alley M, Zaharevitz D, Senderowicz AM. Ann N Y Acad Sci, Inhibition of CDKs as a therapeutic modality.,, 2000, 910,, 207-222, 2. Babu PJ, Narasub ML, Srinivasc K. Arkivoc, Pyridines, pyridazines and guanines as CDK2 inhibitors: a review.,, 2007, 2007,, 247-265, 3. Malumbres M. Genome Biol, Cyclin-dependent kinases.,, 2014, 15,, 122-, 4. Chohan TA, Qian H, Pan Y, Chen JZ. Curr Med Chem, Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents.,, 2015, 22,, 237-263, 5. Malumbres M, Barbacid M. Curr Opin Genet Dev, Cell cycle kinases in cancer.,, 2007, 17,, 60-65,
Cited by
46 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|