Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family.

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Thoma G, Nuninger F, Falchetto R, Hermes E, Tavares GA, Vangrevelinghe E, Zerwes HG

Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family.

J Med Chem. 2011 Jan 13;54(1):284-8. doi: 10.1021/jm101157q. Epub 2010 Dec 14.

PubMed ID
21155605 [ View in PubMed
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Abstract

We describe a synthetic approach toward the rapid modification of phenyl-indolyl maleimides and the discovery of potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family. We provide a rationale for this unprecedented selectivity based on the X-ray crystal structure of an analogue of 1 bound to the ATP-binding site of Jak3. While equally potent compared to the Pfizer pan Jak inhibitor CP-690,550 (2) in an enzymatic Jak3 assay, compound 1 was found to be 20-fold less potent in cellular assays measuring cytokine-triggered signaling through cytokine receptors containing the common gamma chain (gammaC). Contrary to compound 1, compound 2 inhibited Jak1 in addition to Jak3. Permeability and cellular concentrations of compounds 1 and 2 were similar. As Jak3 always cooperates with Jak1 for signaling, we speculate that specific inhibition of Jak3 is not sufficient to efficiently block gammaC cytokine signal transduction required for strong immunosuppression.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TofacitinibNon-receptor tyrosine-protein kinase TYK2IC 50 (nM)176N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK2IC 50 (nM)12N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)8N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)24N/AN/ADetails