7pos: Difference between revisions
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==PI3 kinase delta in complex with 5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-(5-{3-[4-(propan-2-yl)piperazin-1-yl]prop-1-yn-1-yl}pyridin-3-yl)pyridine-3-sulfonamide== | |||
<StructureSection load='7pos' size='340' side='right'caption='[[7pos]], [[Resolution|resolution]] 2.49Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7POS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7POS FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.493Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7XN:5-(3,6-dihydro-2~{H}-pyran-4-yl)-2-methoxy-~{N}-[5-[3-(4-propan-2-ylpiperazin-1-yl)prop-1-ynyl]pyridin-3-yl]pyridine-3-sulfonamide'>7XN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7pos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pos OCA], [https://pdbe.org/7pos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pos RCSB], [https://www.ebi.ac.uk/pdbsum/7pos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pos ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Optimization of a previously reported lead series of PI3Kdelta inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development. | |||
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kdelta with a Novel Binding Mode.,Down K, Amour A, Anderson NA, Barton N, Campos S, Cannons EP, Clissold C, Convery MA, Coward JJ, Doyle K, Duempelfeld B, Edwards CD, Goldsmith MD, Krause J, Mallett DN, McGonagle GA, Patel VK, Rowedder J, Rowland P, Sharpe A, Sriskantharajah S, Thomas DA, Thomson DW, Uddin S, Hamblin JN, Hessel EM J Med Chem. 2021 Sep 23;64(18):13780-13792. doi: 10.1021/acs.jmedchem.1c01102., Epub 2021 Sep 11. PMID:34510892<ref>PMID:34510892</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7pos" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Convery M]] | |||
[[Category: Rowland P]] | |||
Latest revision as of 09:16, 19 June 2024
PI3 kinase delta in complex with 5-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-N-(5-{3-[4-(propan-2-yl)piperazin-1-yl]prop-1-yn-1-yl}pyridin-3-yl)pyridine-3-sulfonamide
Structural highlights
Publication Abstract from PubMedOptimization of a previously reported lead series of PI3Kdelta inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development. Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kdelta with a Novel Binding Mode.,Down K, Amour A, Anderson NA, Barton N, Campos S, Cannons EP, Clissold C, Convery MA, Coward JJ, Doyle K, Duempelfeld B, Edwards CD, Goldsmith MD, Krause J, Mallett DN, McGonagle GA, Patel VK, Rowedder J, Rowland P, Sharpe A, Sriskantharajah S, Thomas DA, Thomson DW, Uddin S, Hamblin JN, Hessel EM J Med Chem. 2021 Sep 23;64(18):13780-13792. doi: 10.1021/acs.jmedchem.1c01102., Epub 2021 Sep 11. PMID:34510892[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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