4HVI

JAK3 kinase domain in complex with 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-oxo-2-piperidin-1-yl-ethyl)-amide

Summary for 4HVI

• Entry DOI: 10.2210/pdb4hvi/pdb
• Related: 4HVD 4HVG 4HVH
• Descriptor: Tyrosine-protein kinase JAK3, 2-cyclopropyl-N-[(2R)-1-oxo-1-(piperidin-1-yl)propan-2-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (3 entities in total)
• Functional Keywords: kinase-inhibitor complex, 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: 35955.01

Authors

Kuglstatter, A.,Shao, A. (deposition date: 2012-11-06, release date: 2013-01-16, Last modification date: 2023-09-20)

Primary citation

Soth, M.,Hermann, J.C.,Yee, C.,Alam, M.,Barnett, J.W.,Berry, P.,Browner, M.F.,Frank, K.,Frauchiger, S.,Harris, S.,He, Y.,Hekmat-Nejad, M.,Hendricks, T.,Henningsen, R.,Hilgenkamp, R.,Ho, H.,Hoffman, A.,Hsu, P.Y.,Hu, D.Q.,Itano, A.,Jaime-Figueroa, S.,Jahangir, A.,Jin, S.,Kuglstatter, A.,Kutach, A.K.,Liao, C.,Lynch, S.,Menke, J.,Niu, L.,Patel, V.,Railkar, A.,Roy, D.,Shao, A.,Shaw, D.,Steiner, S.,Sun, Y.,Tan, S.L.,Wang, S.,Vu, M.D.
3-Amido Pyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1 Selective Inhibitor and Evaluation in Cellular and in Vivo Models.
J.Med.Chem., 56:345-356, 2013

PubMed Abstract: The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

PubMed: 23214979
DOI: 10.1021/jm301646k

Experimental method

X-RAY DIFFRACTION (2.4 Å)