Potent inhibitors of CDK5 derived from roscovitine: synthesis, biological evaluation and molecular modelling.

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Demange L, Abdellah FN, Lozach O, Ferandin Y, Gresh N, Meijer L, Galons H

Potent inhibitors of CDK5 derived from roscovitine: synthesis, biological evaluation and molecular modelling.

Bioorg Med Chem Lett. 2013 Jan 1;23(1):125-31. doi: 10.1016/j.bmcl.2012.10.141. Epub 2012 Nov 10.

PubMed ID

23218601 [ View in PubMed

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Abstract

Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 muM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Seliciclib	Cyclin-dependent kinase 1	IC 50 (nM)	350	N/A	N/A	Details