4PUZ
Crystal structure of spleen tyrosine kinase (Syk) in complex with GS-9973
Summary for 4PUZ
| Entry DOI | 10.2210/pdb4puz/pdb |
| Related | 4PV0 |
| Descriptor | Tyrosine-protein kinase SYK, 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-amine (3 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) |
| Cellular location | Cell membrane (Probable): P43405 |
| Total number of polymer chains | 2 |
| Total formula weight | 68590.93 |
| Authors | Lansdon, E.B.,Mitchell, S.A. (deposition date: 2014-03-14, release date: 2014-04-23, 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 Cited by 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: 24779514DOI: 10.1021/jm500228a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.085 Å) |
Structure validation
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