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

7DCZ の概要

• エントリーDOI: 10.2210/pdb7dcz/pdb
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: bace1, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47360.15

構造登録者

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. (登録日: 2020-10-27, 公開日: 2021-03-10, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)