7dcz | pdb_00007dcz

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

spinqualitylabelsall models 7dcz, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7dcz is a 1 chain structure with sequence from Homo sapiens. 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: GOL, H3C, IOD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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