How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?

0496501 - ÚEB 2019 RIV US eng J - Journal Article
Jorda, Radek - Hendrychová, Denisa - Voller, Jiří - Řezníčková, Eva - Gucký, Tomáš - Kryštof, Vladimír
How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?
Journal of Medicinal Chemistry. Roč. 61, č. 20 (2018), s. 9105-9120. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) LO1204; GA ČR GA17-14007S
Institutional support: RVO:61389030
Keywords : small-molecule inhibitors * metastatic breast-cancer * 1st global approval * thermal shift assay * dna-damage response * in-vitro * androgen receptor * cdk inhibitors * highly potent * 2,6,9-trisubstituted purines
OECD category: Oncology
Impact factor: 6.054, year: 2018

Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited, we evaluated 31 CDKi (claimed to target CDK1-4) for activity toward CDKs 1, 2, 4, 5, 7, 9 and for effects on the cell cycle. Our results suggest that most CDKi should be reclassified as pan-selective and should not be used as a tool. In addition, some compounds did not even inhibit CDKs as their primary cellular targets, for example, NU6140 showed potent inhibition of Aurora kinases. We also established an online database of commercially available CDKi for critical evaluation of their utility as molecular probes. Our results should help researchers select the most relevant chemical tools for their specific applications.
Permanent Link: http://hdl.handle.net/11104/0289264