7dcz

From Proteopedia

(Difference between revisions)

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

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial. J Med Chem. 2021 Feb 25;64(4):1873-1888. PMID:33588527 doi:10.1021/acs.jmedchem.0c01917

1 Structural highlights
2 Publication Abstract from PubMed
3 See Also
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7dcz"

@@ Line 3: / Line 3: @@
 <StructureSection load='7dcz' size='340' side='right'caption='[[7dcz]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7dcz]] 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=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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</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>
-== Function ==
-[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Asada N]]

7dcz

From Proteopedia

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

Structural highlights

Publication Abstract from PubMed

See Also

References

Contents

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