3qaq: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[ | ==Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 1== | ||
<StructureSection load='3qaq' size='340' side='right' caption='[[3qaq]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3qaq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QAQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QAQ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QAQ:[(4-{2-[(3-HYDROXYPHENYL)AMINO]-1H-BENZIMIDAZOL-1-YL}-1,3,5-TRIAZIN-2-YL)AMINO]ACETONITRILE'>QAQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qar|3qar]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qaq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qaq RCSB], [http://www.ebi.ac.uk/pdbsum/3qaq PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kalpha. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41muM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model. | |||
Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.,Peterson EA, Andrews PS, Be X, Boezio AA, Bush TL, Cheng AC, Coats JR, Colletti AE, Copeland KW, Dupont M, Graceffa R, Grubinska B, Harmange JC, Kim JL, Mullady EL, Olivieri P, Schenkel LB, Stanton MK, Teffera Y, Whittington DA, Cai T, La DS Bioorg Med Chem Lett. 2011 Apr 1;21(7):2064-70. Epub 2011 Feb 12. PMID:21376583<ref>PMID:21376583</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]] | *[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]] | [[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]] | ||
[[Category: Tang, J | [[Category: Tang, J]] | ||
[[Category: Whittington, D A | [[Category: Whittington, D A]] | ||
[[Category: Yakowec, P | [[Category: Yakowec, P]] | ||
[[Category: Atp binding]] | [[Category: Atp binding]] | ||
[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
Revision as of 16:34, 9 December 2014
Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 1Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 1
Structural highlights
Publication Abstract from PubMedmTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kalpha. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41muM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model. Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.,Peterson EA, Andrews PS, Be X, Boezio AA, Bush TL, Cheng AC, Coats JR, Colletti AE, Copeland KW, Dupont M, Graceffa R, Grubinska B, Harmange JC, Kim JL, Mullady EL, Olivieri P, Schenkel LB, Stanton MK, Teffera Y, Whittington DA, Cai T, La DS Bioorg Med Chem Lett. 2011 Apr 1;21(7):2064-70. Epub 2011 Feb 12. PMID:21376583[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||