PDBsum entry 4fz7

Transferase/transferase inhibitor

PDB id: 4fz7

Contents

Protein chain

265 a.a.

Ligands

0VH

Waters ×208

PDB id:

4fz7

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of spleen tyrosine kinase complexed with 6-((1r,2s)- 2-amino-cyclohexylamino)-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3- carboxylic acid amide

Structure:

Tyrosine-protein kinase syk. Chain: a. Fragment: residues 365-635, protein kinase domain. 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:

1.75Å R-factor: 0.202 R-free: 0.250

Authors:

A.Kuglstatter,M.Slade

Key ref:

M.C.Lucas et al. (2014). Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors. J Med Chem, 57, 2683-2691. PubMed id: 24520947 DOI: 10.1021/jm401982j

Date:

06-Jul-12 Release date: 10-Jul-13

Protein chain

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

Seq: 635 a.a.

Struc: 265 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/jm401982j

J Med Chem 57:2683-2691 (2014)

PubMed id: 24520947

Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

M.C.Lucas, N.Bhagirath, E.Chiao, D.M.Goldstein, J.C.Hermann, P.Y.Hsu, S.Kirchner, J.J.Kennedy-Smith, A.Kuglstatter, C.Lukacs, J.Menke, L.Niu, F.Padilla, Y.Peng, L.Polonchuk, A.Railkar, M.Slade, M.Soth, D.Xu, P.Yadava, C.Yee, M.Zhou, C.Liao.

ABSTRACT

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.