| Structural highlights
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.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ 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
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