Journal Article

DZNE-2026-00070

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.

Tschirner, S. K. (First author)DZNE* ; Schmidt, A.DZNE* ; Ito, M. ; Hyakkoku, K. ; Yoshimura, A. ; Müller, S. A.DZNE* ; Horiguchi, N. ; Lichtenthaler, S. F. (Last author)DZNE*

2026
Wiley VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/pmic.70082

Abstract: The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co-inhibition of the BACE1-homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM-1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non-human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM-1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.

Keyword(s): Amyloid Precursor Protein Secretases: antagonists & inhibitors (MeSH) ; Amyloid Precursor Protein Secretases: cerebrospinal fluid (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: antagonists & inhibitors (MeSH) ; Aspartic Acid Endopeptidases: cerebrospinal fluid (MeSH) ; Male (MeSH) ; Humans (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Vascular Cell Adhesion Molecule-1: cerebrospinal fluid (MeSH) ; Macaca fascicularis (MeSH) ; Amyloid Precursor Protein Secretases ; Aspartic Acid Endopeptidases ; BACE1 protein, human ; Biomarkers ; Vascular Cell Adhesion Molecule-1

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Nalbach, K.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Elenbecestat and compound 89 potently inhibit BACE1 but not BACE2 when subchronically dosed in non-human primates (Project PXD067461)
PRoteomics IDEntifications Database (2025)2025   Fulltext BibTeX | EndNote: XML, Text | RIS

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Nalbach, K.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Elenbecestat and compound 89 potently inhibit BACE1 but not BACE2 when subchronically dosed in non-human primates (Project PXD067413)
PRoteomics IDEntifications Database (2025)2025   Fulltext BibTeX | EndNote: XML, Text | RIS

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