3PJC

Crystal structure of JAK3 complexed with a potent ATP site inhibitor showing high selectivity within the Janus kinase family

Summary for 3PJC

• Entry DOI: 10.2210/pdb3pjc/pdb
• Descriptor: Tyrosine-protein kinase JAK3, 3-(1H-indol-3-yl)-4-[2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrrole-2,5-dione (3 entities in total)
• Functional Keywords: small molecule inhibitor, atp site kinase inhibitor, atp-binding, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endomembrane system; Peripheral membrane protein (By similarity): P52333
• Total number of polymer chains: 1
• Total formula weight: 36152.14

Authors

Tavares, G.A.,Thoma, G.,Zerwes, H.-G.,Kroemer, M. (deposition date: 2010-11-09, release date: 2010-12-29, Last modification date: 2024-02-21)

Primary citation

Thoma, G.,Nuninger, F.,Falchetto, R.,Hermes, E.,Tavares, G.A.,Vangrevelinghe, E.,Zerwes, H.G.
Identification of a Potent Janus Kinase 3 Inhibitor with High Selectivity within the Janus Kinase Family.
J.Med.Chem., 54:284-288, 2011

PubMed 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.

PubMed: 21155605
DOI: 10.1021/jm101157q

Experimental method

X-RAY DIFFRACTION (2.2 Å)