PDBsum entry 5cxh

Transferase/transferase inhibitor

PDB id: 5cxh

Contents

Protein chain

277 a.a.

Ligands

55M

Waters ×214

PDB id:

5cxh

Name:

Transferase/transferase inhibitor

Title:

Syk catalytic domain complexed with a potent orally bioavailable thiazole inhibitor

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: protein kinase domain residues 356-635. Synonym: spleen tyrosine kinase,p72-syk. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.90Å R-factor: 0.176 R-free: 0.205

Authors:

C.C.Lee

Key ref:

G.Thoma et al. (2015). Orally bioavailable Syk inhibitors with activity in a rat PK/PD model. Bioorg Med Chem Lett, 25, 4642-4647. PubMed id: 26320624 DOI: 10.1016/j.bmcl.2015.08.037

Date:

29-Jul-15 Release date: 23-Sep-15

Protein chain

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

Seq: 635 a.a.

Struc: 277 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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: 10.1016/j.bmcl.2015.08.037

Bioorg Med Chem Lett 25:4642-4647 (2015)

PubMed id: 26320624

Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.

G.Thoma, S.Veenstra, R.Strang, J.Blanz, E.Vangrevelinghe, J.Berghausen, C.C.Lee, H.G.Zerwes.

ABSTRACT

Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.