PDBsum entry 4wnm

Transferase/transferase inhibitor

PDB id: 4wnm

Contents

Protein chain

273 a.a.

Ligands

3RT

SO4

Waters ×16

PDB id:

4wnm

Name:

Transferase/transferase inhibitor

Title:

Syk catalytic domain in complex with a potent triazolopyridine inhibitor

Structure:

Tyrosine-protein kinase syk. Chain: a. 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:

2.50Å R-factor: 0.207 R-free: 0.260

Authors:

P.J.Jackson

Key ref:

G.D.Ferguson et al. (2016). A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation. Plos One, 11, e0145705. PubMed id: 26756335 DOI: 10.1371/journal.pone.0145705

Date:

13-Oct-14 Release date: 20-Jan-16

Protein chain

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

Seq: 635 a.a.

Struc: 273 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1371/journal.pone.0145705

Plos One 11:e0145705 (2016)

PubMed id: 26756335

A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.

G.D.Ferguson, M.Delgado, V.Plantevin-Krenitsky, K.Jensen-Pergakes, R.J.Bates, S.Torres, M.Celeridad, H.Brown, K.Burnett, L.Nadolny, L.Tehrani, G.Packard, B.Pagarigan, J.Haelewyn, T.Nguyen, L.Xu, Y.Tang, M.Hickman, F.Baculi, S.Pierce, K.Miyazawa, P.Jackson, P.Chamberlain, L.LeBrun, W.Xie, B.Bennett, K.Blease.

ABSTRACT

Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.