2ofu

From Proteopedia

---

Revision as of 21:03, 12 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 2ofu, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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)ami, no)-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.

Disease

Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]

About this Structure

2OFU is a Single protein structure of sequence from Homo sapiens with SO4 and 1N9 as ligands. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.

Reference

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity., Martin MW, Newcomb J, Nunes JJ, McGowan DC, Armistead DM, Boucher C, Buchanan JL, Buckner W, Chai L, Elbaum D, Epstein LF, Faust T, Flynn S, Gallant P, Gore A, Gu Y, Hsieh F, Huang X, Lee JH, Metz D, Middleton S, Mohn D, Morgenstern K, Morrison MJ, Novak PM, Oliveira-dos-Santos A, Powers D, Rose P, Schneider S, Sell S, Tudor Y, Turci SM, Welcher AA, White RD, Zack D, Zhao H, Zhu L, Zhu X, Ghiron C, Amouzegh P, Ermann M, Jenkins J, Johnston D, Napier S, Power E, J Med Chem. 2006 Aug 10;49(16):4981-91. PMID:16884310

Page seeded by OCA on Mon Nov 12 23:10:24 2007