%0 Journal Article
%A Tschirner, Sarah K
%A Schmidt, Andree
%A Ito, Mana
%A Hyakkoku, Kana
%A Yoshimura, Akimasa
%A Müller, Stephan A
%A Horiguchi, Naotaka
%A Lichtenthaler, Stefan F
%T Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.
%J Proteomics
%V 26
%N 1
%@ 1615-9853
%C Weinheim
%I Wiley VCH
%M DZNE-2026-00070
%P 100 - 107
%D 2026
%X 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.
%K Amyloid Precursor Protein Secretases: antagonists & inhibitors
%K Amyloid Precursor Protein Secretases: cerebrospinal fluid
%K Animals
%K Aspartic Acid Endopeptidases: antagonists & inhibitors
%K Aspartic Acid Endopeptidases: cerebrospinal fluid
%K Male
%K Humans
%K Biomarkers: cerebrospinal fluid
%K Vascular Cell Adhesion Molecule-1: cerebrospinal fluid
%K Macaca fascicularis
%K Amyloid Precursor Protein Secretases (NLM Chemicals)
%K Aspartic Acid Endopeptidases (NLM Chemicals)
%K BACE1 protein, human (NLM Chemicals)
%K Biomarkers (NLM Chemicals)
%K Vascular Cell Adhesion Molecule-1 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41310967
%2 pmc:PMC12809003
%R 10.1002/pmic.70082
%U https://pub.dzne.de/record/284027