PDBsum entry 4i0s

Transferase/transferase inhibitor

PDB id: 4i0s

Contents

Protein chain

267 a.a.

Ligands

1B5

Waters ×106

PDB id:

4i0s

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of spleen tyrosine kinase complexed with 2-(6- chloro-1-methyl-1h-indazol-3-yl)-5h-pyrrolo[2,3-b]pyrazine-7- carboxylic acid isopropylamide

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: protein kinase domain (unp residues 356-635). 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:

1.98Å R-factor: 0.218 R-free: 0.236

Authors:

A.Kuglstatter,M.Slade

Key ref:

F.Padilla et al. (2013). Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors. J Med Chem, 56, 1677-1692. PubMed id: 23350847 DOI: 10.1021/jm301720p

Date:

19-Nov-12 Release date: 30-Oct-13

Protein chain

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

Seq: 635 a.a.

Struc: 267 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/jm301720p

J Med Chem 56:1677-1692 (2013)

PubMed id: 23350847

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.

F.Padilla, N.Bhagirath, S.Chen, E.Chiao, D.M.Goldstein, J.C.Hermann, J.Hsu, J.J.Kennedy-Smith, A.Kuglstatter, C.Liao, W.Liu, L.E.Lowrie, K.C.Luk, S.M.Lynch, J.Menke, L.Niu, T.D.Owens, C.O-Yang, A.Railkar, R.C.Schoenfeld, M.Slade, S.Steiner, Y.C.Tan, A.G.Villaseñor, C.Wang, J.Wanner, W.Xie, D.Xu, X.Zhang, M.Zhou, M.C.Lucas.

ABSTRACT

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.