PDBsum entry 4pv0

Transferase/transferase inhibitor

PDB id: 4pv0

Contents

Protein chain

268 a.a.

Ligands

CG4

Metals

_CL ×5

Waters ×71

PDB id:

4pv0

Name:

Transferase/transferase inhibitor

Title:

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

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: syk kinase domain, unp residues 363-635. Synonym: spleen tyrosine kinase, p72-syk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.00Å R-factor: 0.231 R-free: 0.282

Authors:

E.B.Lansdon,S.A.Mitchell

Key ref:

K.S.Currie et al. (2014). Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem, 57, 3856-3873. PubMed id: 24779514 DOI: 10.1021/jm500228a

Date:

14-Mar-14 Release date: 21-May-14

Protein chain

P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK from Homo sapiens

Seq: 635 a.a.

Struc: 268 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm500228a

J Med Chem 57:3856-3873 (2014)

PubMed id: 24779514

Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase.

K.S.Currie, J.E.Kropf, T.Lee, P.Blomgren, J.Xu, Z.Zhao, S.Gallion, J.A.Whitney, D.Maclin, E.B.Lansdon, P.Maciejewski, A.M.Rossi, H.Rong, J.Macaluso, J.Barbosa, J.A.Di Paolo, S.A.Mitchell.

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.