PDBsum entry 2ofu

Transferase

PDB id: 2ofu

Contents

Protein chain

273 a.a. *

Ligands

SO4

1N9

Waters ×312

* Residue conservation analysis

PDB id:

2ofu

Name:

Transferase

Title:

X-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to lck

Structure:

Proto-oncogene tyrosine-protein kinase lck. Chain: a. Fragment: lck kinase domain, residues 229-501. Synonym: p56-lck, lymphocyte cell-specific protein-tyrosine kinase, lsk, t cell- specific protein-tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lck. Expressed in: insect cell.

Resolution:

2.00Å R-factor: 0.228 R-free: 0.291

Authors:

X.Huang

Key ref:

M.W.Martin et al. (2006). Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity. J Med Chem, 49, 4981-4991. PubMed id: 16884310 DOI: 10.1021/jm060435i

Date:

04-Jan-07 Release date: 27-Feb-07

Protein chain

P06239  (LCK_HUMAN) -  Tyrosine-protein kinase Lck from Homo sapiens

Seq: 509 a.a.

Struc: 273 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/jm060435i

J Med Chem 49:4981-4991 (2006)

PubMed id: 16884310

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.

M.W.Martin, J.Newcomb, J.J.Nunes, D.C.McGowan, D.M.Armistead, C.Boucher, J.L.Buchanan, W.Buckner, L.Chai, D.Elbaum, L.F.Epstein, T.Faust, S.Flynn, P.Gallant, A.Gore, Y.Gu, F.Hsieh, X.Huang, J.H.Lee, D.Metz, S.Middleton, D.Mohn, K.Morgenstern, M.J.Morrison, P.M.Novak, A.Oliveira-dos-Santos, D.Powers, P.Rose, S.Schneider, S.Sell, Y.Tudor, S.M.Turci, A.A.Welcher, R.D.White, D.Zack, H.Zhao, L.Zhu, X.Zhu, C.Ghiron, P.Amouzegh, M.Ermann, J.Jenkins, D.Johnston, S.Napier, E.Power.

ABSTRACT

The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.