% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Tschirner:284027,
      author       = {Tschirner, Sarah K and Schmidt, Andree and Ito, Mana and
                      Hyakkoku, Kana and Yoshimura, Akimasa and Müller, Stephan A
                      and Horiguchi, Naotaka and Lichtenthaler, Stefan F},
      title        = {{E}lenbecestat and {C}ompound 89 {P}otently {I}nhibit
                      {BACE}1 but {N}ot {BACE}2 {W}hen {S}ubchronically {D}osed in
                      {N}on-{H}uman {P}rimates.},
      journal      = {Proteomics},
      volume       = {26},
      number       = {1},
      issn         = {1615-9853},
      address      = {Weinheim},
      publisher    = {Wiley VCH},
      reportid     = {DZNE-2026-00070},
      pages        = {100 - 107},
      year         = {2026},
      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.},
      keywords     = {Amyloid Precursor Protein Secretases: antagonists $\&$
                      inhibitors / Amyloid Precursor Protein Secretases:
                      cerebrospinal fluid / Animals / Aspartic Acid
                      Endopeptidases: antagonists $\&$ inhibitors / Aspartic Acid
                      Endopeptidases: cerebrospinal fluid / Male / Humans /
                      Biomarkers: cerebrospinal fluid / Vascular Cell Adhesion
                      Molecule-1: cerebrospinal fluid / Macaca fascicularis /
                      Amyloid Precursor Protein Secretases (NLM Chemicals) /
                      Aspartic Acid Endopeptidases (NLM Chemicals) / BACE1
                      protein, human (NLM Chemicals) / Biomarkers (NLM Chemicals)
                      / Vascular Cell Adhesion Molecule-1 (NLM Chemicals)},
      cin          = {AG Lichtenthaler},
      ddc          = {540},
      cid          = {I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41310967},
      pmc          = {pmc:PMC12809003},
      doi          = {10.1002/pmic.70082},
      url          = {https://pub.dzne.de/record/284027},
}