Evidence map›Paper›PMID 40399225›Full record

ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2025

Discovery of an APP-selective BACE1 inhibitor for Alzheimer's disease.

Jesus Campagna, Barbara Jagodzinska, Dongwook Wi, Chunni Zhu, Jessica Lee, Whitaker Cohn, Michael Jun, Chris Elias, Samar Padder, Olivier Descamps and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Jesus CampagnaDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Barbara JagodzinskaDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Dongwook WiDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Chunni ZhuDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Jessica LeeDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Whitaker CohnDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Michael JunDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Chris EliasDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Samar PadderDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Olivier DescampsBuck Institute for Research on Aging, Novato, CA, 94945, USA.
Clare Peters-LibeuBuck Institute for Research on Aging, Novato, CA, 94945, USA.
Qiang ZhangBuck Institute for Research on Aging, Novato, CA, 94945, USA.
Olivia GorostizaBuck Institute for Research on Aging, Novato, CA, 94945, USA.
Karen PoksayBuck Institute for Research on Aging, Novato, CA, 94945, USA.
Patricia SpilmanDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA.
Dale BredesenDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA; Buck Institute for Research on Aging, Novato, CA, 94945, USA.
Varghese JohnDrug Discovery Lab (DDL), Department of Neurology, Easton Center for Alzheimer's Disease Research and Care, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, 90095, USA. Electronic address: vjohn@mednet.ucla.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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 glycoprotein ligand-1 (PSGL1). FAH65 shows little inhibitory activity against other aspartyl proteases cathepsin D (Cat D) and BACE2. FAH65 reduces BACE1 cleavage products soluble APPβ (sAPPβ) and the β C-terminal fragment (βCTF), as well as amyloid-β (Aβ) 1-40 and 1-42, both in vitro in cells and in vivo in an animal model of AD. In a murine model of AD, FAH65 improved the discrimination score in the Novel Object Recognition (NOR) memory testing paradigm. The active enantiomer of racemate FAH65, FAH65E(-), displays good brain-penetrance and target engagement, meriting further pre-clinical development as an ASBI that may reduce Aβ levels and overcome the deleterious effects of the non-selective BACE1 inhibitors that have failed in the clinic. FAH65E(-) has the potential to be a first-in-class oral therapy that could be used in conjunction with an approved anti-Aβ antibody therapy for AD.

Indexed as

Alzheimer DiseaseAmyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesDrug DiscoveryAmyloid beta-PeptidesAnimalsHumansMiceMice, Inbred C57BLMice, TransgenicAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesBACE1 protein, humanAPP-selectiveASBIBACE1 inhibitorFAH65

Identifiers

PMID40399225
PMCPMC12491701

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.