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

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