biostudies-literatureUnknown22(5)Campagna JInhibition of amyloid precursor protein (APP) beta-site cleaving enzyme 1 (BACE1) has been a target for Alzheimer's disease (AD) therapeutic development. Here, we report our identification of APP-selective BACE1 (ASBI) inhibitors that are selective for APP as the substrate and BACE1 as the target enzyme. A known fluoro aminohydantoin (FAH) inhibitor compound was identified by screening a compound library for inhibition of BACE1 cleavage of a maltose binding protein (MBP)-conjugated-APPC125 substrate followed by optimization and IC50 determination using the P5-P5' activity assay. Optimization of the screening hit led to candidate FAH65, which displays selectivity for inhibition of APP cleavage with little activity against other BACE1 substrates neuregulin 1 (NRG1) or p-selectin glycoproteinNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeuticse00610https://www.ebi.ac.uk/biostudies/studies/S-EPMC12491701biostudies-literatureDiscovery of an APP-selective BACE1 inhibitor for Alzheimer's disease.PMC12491701Poksay KCampagna JDescamps OBredesen DLee JCohn WPeters-Libeu CZhang QZhu CJagodzinska BSpilman PJohn VJun MElias CGorostiza OPadder SWi DfalseDiscovery of an APP-selective BACE1 inhibitor for Alzheimer's disease.Inhibition of amyloid precursor protein (APP) beta-site cleaving enzyme 1 (BACE1) has been a target for Alzheimer's disease (AD) therapeutic development. Here, we report our identification of APP-selective BACE1 (ASBI) inhibitors that are selective for APP as the substrate and BACE1 as the target enzyme. A known fluoro aminohydantoin (FAH) inhibitor compound was identified by screening a compound library for inhibition of BACE1 cleavage of a maltose binding protein (MBP)-conjugated-APPC125 substrate followed by optimization and IC50 determination using the P5-P5' activity assay. Optimization of the screening hit led to candidate FAH65, which displays selectivity for inhibition of APP cleavage with little activity against other BACE1 substrates neuregulin 1 (NRG1) or p-selectin glycoprotein2025-01-01T00:00:00Z2025 Sep2026-06-04T02:00:46.571Z2026-05-04T03:13:22.029ZS-EPMC124917014039922510.1016/j.neurot.2025.e00610