4PV0

Crystal structure of spleen tyrosine kinase (Syk) in complex with an imidazopyrazine inhibitor

Summary for 4PV0

• Entry DOI: 10.2210/pdb4pv0/pdb
• Related: 4PUZ
• Descriptor: Tyrosine-protein kinase SYK, 4-[(3-{8-[(3,4-dimethoxyphenyl)amino]imidazo[1,2-a]pyrazin-6-yl}benzoyl)amino]benzoic acid, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: syk, spleen tyrosine kinase, kinase inhibitor, protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32542.50

Authors

Lansdon, E.B.,Mitchell, S.A. (deposition date: 2014-03-14, release date: 2014-05-21, Last modification date: 2023-09-20)

Primary citation

Currie, K.S.,Kropf, J.E.,Lee, T.,Blomgren, P.,Xu, J.,Zhao, Z.,Gallion, S.,Whitney, J.A.,Maclin, D.,Lansdon, E.B.,Maciejewski, P.,Rossi, A.M.,Rong, H.,Macaluso, J.,Barbosa, J.,Di Paolo, J.A.,Mitchell, S.A.
Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase.
J.Med.Chem., 57:3856-3873, 2014

PubMed Abstract: Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.

PubMed: 24779514
DOI: 10.1021/jm500228a

Experimental method

X-RAY DIFFRACTION (2 Å)