7DCZ

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

Summary for 7DCZ

• Entry DOI: 10.2210/pdb7dcz/pdb
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: bace1, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47360.15

Authors

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, K.I.,Kato, A.,Sakaguchi, G. (deposition date: 2020-10-27, release date: 2021-03-10, Last modification date: 2024-10-16)

Primary citation

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, K.I.,Kato, A.,Sakaguchi, G.
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.
J.Med.Chem., 64:1873-1888, 2021

PubMed Abstract: Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ 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 (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 demonstrated robust and dose-dependent Aβ 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.

PubMed: 33588527
DOI: 10.1021/acs.jmedchem.0c01917

Experimental method

X-RAY DIFFRACTION (2.3 Å)