TY  - JOUR
AU  - Tschirner, Sarah K
AU  - Schmidt, Andree
AU  - Ito, Mana
AU  - Hyakkoku, Kana
AU  - Yoshimura, Akimasa
AU  - Müller, Stephan A
AU  - Horiguchi, Naotaka
AU  - Lichtenthaler, Stefan F
TI  - Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates.
JO  - Proteomics
VL  - 26
IS  - 1
SN  - 1615-9853
CY  - Weinheim
PB  - Wiley VCH
M1  - DZNE-2026-00070
SP  - 100 - 107
PY  - 2026
AB  - 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.
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Amyloid Precursor Protein Secretases: cerebrospinal fluid
KW  - Animals
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: cerebrospinal fluid
KW  - Male
KW  - Humans
KW  - Biomarkers: cerebrospinal fluid
KW  - Vascular Cell Adhesion Molecule-1: cerebrospinal fluid
KW  - Macaca fascicularis
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Vascular Cell Adhesion Molecule-1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41310967
C2  - pmc:PMC12809003
DO  - DOI:10.1002/pmic.70082
UR  - https://pub.dzne.de/record/284027
ER  -