8ff8
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8ff8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FF8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FF8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8ff8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FF8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FF8 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XV0:2-(4-cyanoanilino)-N-(4-phenylpyridin-3-yl)pyrimidine-4-carboxamide'>XV0</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.33Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XV0:2-(4-cyanoanilino)-N-(4-phenylpyridin-3-yl)pyrimidine-4-carboxamide'>XV0</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=8ff8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ff8 OCA], [https://pdbe.org/8ff8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ff8 RCSB], [https://www.ebi.ac.uk/pdbsum/8ff8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ff8 ProSAT]</span></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=8ff8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ff8 OCA], [https://pdbe.org/8ff8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ff8 RCSB], [https://www.ebi.ac.uk/pdbsum/8ff8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ff8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3beta in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model. | Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3beta in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model. | ||
| - | Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.,Hartz RA, Ahuja VT, Luo G, Chen L, Sivaprakasam P, Xiao H, Krause CM, Clarke WJ, Xu S, Tokarski JS, Kish K, Lewis H, Szapiel N, Ravirala R, Mutalik S, Nakmode D, Shah D, Burton CR, Macor JE, Dubowchik GM J Med Chem. 2023 | + | Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.,Hartz RA, Ahuja VT, Luo G, Chen L, Sivaprakasam P, Xiao H, Krause CM, Clarke WJ, Xu S, Tokarski JS, Kish K, Lewis H, Szapiel N, Ravirala R, Mutalik S, Nakmode D, Shah D, Burton CR, Macor JE, Dubowchik GM J Med Chem. 2023 Jun 8;66(11):7534-7552. doi: 10.1021/acs.jmedchem.3c00364. Epub , 2023 May 26. PMID:37235865<ref>PMID:37235865</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
CRYSTAL STRUCTURE OF GLYCOGEN SYNTHASE KINASE 3 BETA COMPLEXED WITH 2-[(4-CYANOPHENYL)AMINO]-N-(4-PHENYLPYRIDIN-3-YL)PYRIMIDINE-4-CARBOXAMIDE
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