title: Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family.
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 γ chain (γC). 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 γC cytokine signal transduction required for strong immunosuppression.
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, Basel, Switzerland. gebhard.thoma@novartis.com
authors.forename: Gebhard
authors.initials: G
authors.lastname: Thoma
authors.forename: Francois
authors.initials: F
authors.lastname: Nuninger
authors.forename: Rocco
authors.initials: R
authors.lastname: Falchetto
authors.forename: Erwin
authors.initials: E
authors.lastname: Hermes
authors.forename: Gisele A
authors.initials: GA
authors.lastname: Tavares
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Hans-Günter
authors.initials: HG
authors.lastname: Zerwes
mesh_terms: D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C562244:3-(5-(4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl)-2-trifluoromethylphenyl)-4-(1H-indol-3-yl)pyrrole-2,5-dione; D007166:Immunosuppressive Agents; D007211:Indoles; D008301:Maleimides; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C479163:tofacitinib; D053613:Janus Kinase 1; D053616:Janus Kinase 3