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@MISC{Nalbach:282934,
      author       = {Nalbach, Karsten and Lichtenthaler, Stefan},
      title        = {{D}ataset: {E}lenbecestat and compound 89 potently inhibit
                      {BACE}1 but not {BACE}2 when subchronically dosed in
                      non-human primates ({P}roject {PXD}067413)},
      publisher    = {PRoteomics IDEntifications Database},
      reportid     = {DZNE-2025-01395},
      year         = {2025},
      abstract     = {The beta-secretase BACE1 (beta-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 beta (Abeta) 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.},
      cin          = {AG Lichtenthaler},
      cid          = {I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)32},
      url          = {https://pub.dzne.de/record/282934},
}