Inhibitor selectivity for cyclin-dependent kinase 7: a structural, thermodynamic, and modelling study
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.
Date Issued
2017-01-26
Date Acceptance
2017-01-25
Citation
Chemmedchem, 2017, 12 (5), pp.372-380
ISSN
1860-7187
Publisher
Wiley
Start Page
372
End Page
380
Journal / Book Title
Chemmedchem
Volume
12
Issue
5
Copyright Statement
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the accepted version of the following article, which has been published in final form at http://dx.doi.org/10.1002/cmdc.201600535
Identifier
http://www.ncbi.nlm.nih.gov/pubmed/28125165
Subjects
CDK7
cancer
drug discovery
isothermal titration calorimetry
protein kinases
Medicinal & Biomolecular Chemistry
0304 Medicinal And Biomolecular Chemistry
0305 Organic Chemistry
1115 Pharmacology And Pharmaceutical Sciences
Publication Status
Published
Coverage Spatial
Germany