7dcz
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==Crystal Structure of BACE1 in complex with N-{3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4- fluorophenyl}-5-cyanopyridine-2-carboxamide== | ==Crystal Structure of BACE1 in complex with N-{3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4- fluorophenyl}-5-cyanopyridine-2-carboxamide== | ||
| - | <StructureSection load='7dcz' size='340' side='right'caption='[[7dcz]]' scene=''> | + | <StructureSection load='7dcz' size='340' side='right'caption='[[7dcz]], [[Resolution|resolution]] 2.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DCZ FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DCZ FirstGlance]. <br> | ||
| - | </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=7dcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dcz OCA], [https://pdbe.org/7dcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dcz RCSB], [https://www.ebi.ac.uk/pdbsum/7dcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dcz ProSAT]</span></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]] 2.3Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=H3C:N-[3-[(4S)-2-azanyl-4-methyl-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide'>H3C</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=7dcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dcz OCA], [https://pdbe.org/7dcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dcz RCSB], [https://www.ebi.ac.uk/pdbsum/7dcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dcz ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Accumulation of amyloid beta peptides (Abeta) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Abeta production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Abeta reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening. | ||
| + | |||
| + | Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based beta-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial.,Koriyama Y, Hori A, Ito H, Yonezawa S, Baba Y, Tanimoto N, Ueno T, Yamamoto S, Yamamoto T, Asada N, Morimoto K, Einaru S, Sakai K, Kanazu T, Matsuda A, Yamaguchi Y, Oguma T, Timmers M, Tritsmans L, Kusakabe KI, Kato A, Sakaguchi G J Med Chem. 2021 Feb 25;64(4):1873-1888. doi: 10.1021/acs.jmedchem.0c01917. Epub , 2021 Feb 15. PMID:33588527<ref>PMID:33588527</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7dcz" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal Structure of BACE1 in complex with N-{3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4- fluorophenyl}-5-cyanopyridine-2-carboxamide
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Categories: Large Structures | Asada N | Baba Y | Einaru S | Hori A | Ito H | Kanazu T | Kato A | Koriyama Y | Kusakabe KI | Matsuda A | Morimoto K | Oguma T | Sakaguchi G | Sakai K | Tanimoto N | Timmers M | Tritsmans L | Ueno T | Yamaguchi Y | Yamamoto S | Yamamoto T | Yonezawa S
