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

Thoma, Gebhard, Nuninger, Francois, Falchetto, Rocco Angelo, Hermes, Erwin, Tavares, Gisele, 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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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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