2ofu
From Proteopedia
(New page: 200px<br /> <applet load="2ofu" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ofu, resolution 2.00Å" /> '''x-ray crystal struc...) |
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| - | [[Image:2ofu.gif|left|200px]]<br /> | + | [[Image:2ofu.gif|left|200px]]<br /><applet load="2ofu" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2ofu" size=" | + | |
caption="2ofu, resolution 2.00Å" /> | caption="2ofu, resolution 2.00Å" /> | ||
'''x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck'''<br /> | '''x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of | + | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2OFU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and 1N9 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http:// | + | 2OFU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=1N9:'>1N9</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OFU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: lck]] | [[Category: lck]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:18:03 2008'' |
Revision as of 16:18, 21 February 2008
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x-ray crystal structure of 2-aminopyrimidine carbamate 43 bound to Lck
Contents |
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 and 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
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