9cdy
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 9cdy is ON HOLD Authors: Skene, R.J., Bell, J.A. Description: Crystal structure of DLK with inhibitor bound Category: Unreleased Structures [[C...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of DLK with inhibitor bound== | |
| + | <StructureSection load='9cdy' size='340' side='right'caption='[[9cdy]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9cdy]] is a 1 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=9CDY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CDY 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]] 1.5Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AZ8:3-{(3M)-3-[6-amino-5-(trifluoromethoxy)pyridin-3-yl]-1-ethyl-7-oxo-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl}-1,5-anhydro-3,4-dideoxy-2-O-methyl-D-erythro-pentitol'>A1AZ8</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9cdy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9cdy OCA], [https://pdbe.org/9cdy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9cdy RCSB], [https://www.ebi.ac.uk/pdbsum/9cdy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9cdy ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/M3K12_HUMAN M3K12_HUMAN] May be an activator of the JNK/SAPK pathway. Phosphorylates beta-casein, histone 1 and myelin basic protein in vitro. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program's progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model. | ||
| - | + | In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.,Lagiakos HR, Zou Y, Igawa H, Therrien E, Lawrenz M, Kato M, Svensson M, Gray F, Jensen K, Dahlgren MK, Pelletier RD, Dingley K, Bell JA, Liu Z, Jiang Y, Zhou H, Skene RJ, Nie Z J Med Chem. 2025 Feb 13;68(3):2720-2741. doi: 10.1021/acs.jmedchem.4c02074. Epub , 2024 Dec 13. PMID:39670820<ref>PMID:39670820</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9cdy" style="background-color:#fffaf0;"></div> |
| - | [[Category: Bell | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bell JA]] | ||
| + | [[Category: Skene RJ]] | ||
Current revision
Crystal structure of DLK with inhibitor bound
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