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Identification of a potent Jak3 inhibitor with high selectivity within the Jak kinase family

Thoma, Gebhard and Nuninger, Francois and Falchetto, Rocco Angelo and Hermes, Erwin and Tavares, Gisele and Vangrevelinghe, Eric and Zerwes, Hans-Guenter (2011) Identification of a potent Jak3 inhibitor with high selectivity within the Jak kinase family. The Journal of Medicinal Chemistry, 54 (1). pp. 284-288. ISSN 0022-2623

Abstract

We describe a synthetic approach towards the rapid modification of phenyl-indolyl maleimides and the discovery of the highly potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family. We provide a rational for this unprecedented selectivity based on the X-ray crystal structure of an analog of 1 bound to the ATP-binding site of Jak3. While equally potent compared to the Pfizer pan Jak inhibitor CP-690,550 in an enzymatic Jak3 assay compound 1 was found to be substantially less potent in cellular assays measuring cytokine-triggered signaling through cytokine receptors containing the common gamma chain (C). Contrary to compound 1, CP-690,550 inhibited Jak1 in addition to Jak3. Similar cell-associated amounts of compound 1 and CP-690,550 were determined. As Jak3 always cooperates with Jak1 for signaling we speculate that the specific inhibition of Jak3 is insufficient to block C cytokine signal transduction required for strong immunosuppression.

Item Type: Article
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Additional Information: archiving not formally supported by this publisher
Keywords: Jak3, Jak1, kinase inhibitor, CP-690,550
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2988

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