Evidence map›Paper›PMID 40322539›Full record

Articlenpj drug discovery2025

Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer's disease mice.

Whitaker Cohn, Jesus Campagna, Dongwook Wi, Jessica T Lee, Sahiba Beniwal, Gazmend Elezi, Chunni Zhu, Barbara Jagodzinska, Julian Whitelegge, Robert Damoiseaux and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in npj drug discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Article
  2. Review
  3. Leveraging Artificial Intelligence and Large Language Models for Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Review
  4. Review
  5. 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

11 authors.

Whitaker CohnThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Jesus CampagnaThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Dongwook WiThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Jessica T LeeThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Sahiba BeniwalThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Gazmend EleziPasarow Mass Spectrometry Laboratory, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, 760 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Chunni ZhuThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Barbara JagodzinskaThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Julian WhiteleggePasarow Mass Spectrometry Laboratory, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, 760 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.
Robert DamoiseauxDepartment of Molecular and Medical Pharmacology, 650 Charles E. Young Drive, University of California Los Angeles, Los Angeles, USA.
Varghese JohnThe Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, 710 Westwood Plaza, University of California Los Angeles, Los Angeles, USA.

Funding

Screening for enhancers of secreted clusterin (sCLU) and evaluation in AD modelsR21AG072150 · NIA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JOHN, VARGHESE · 2021 to 2021
$423k
NIA NIH HHS R21 AG072150
6 · The paper itself

Abstract

Despite substantial research and drug discovery efforts, Alzheimer's Disease (AD) remains the sixth leading cause of death in the United States, underscoring the urgent need for novel therapeutic targets. A mutation in the clusterin (CLU) gene that hinders expression of the cyto-protective secreted isoform of clusterin (sCLU) that affects the aggregation and clearance of two key proteins implicated in AD, Aβ and tau, is the third most significant genetic risk factor for late-onset AD. Here, we present findings from our drug discovery program to identify small molecules that enhance sCLU levels and assess their impact on AD pathology and cognition in a murine model of AD. A high-throughput screening campaign identified two classes of epigenetic modulators that increase sCLU levels with subsequent medicinal chemistry efforts leading to bromodomain and extra-terminal (BET) inhibitor new chemical entities (NCEs) with enhanced potency, drug-like properties, and oral brain bioavailability. The lead candidate NCE, DDL-357, increased brain sCLU in the murine ApoE4TR-5XFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3xTg-AD model, DDL-357 reduced phospho-tau in brain and led to improvements in mouse performance and memory in the Barnes maze testing paradigm. Proteomic analysis of brain tissue from both AD models revealed changes in proteins involved in mitochondrial function and synaptic plasticity. These findings reveal the potential of sCLU enhancement as a target for therapeutic development in AD and support the continued development of the preclinical lead candidate.

Indexed as

BiomarkersDrug screeningMedicinal chemistryTarget validation

Identifiers

PMID40322539
PMCPMC12048343

What OpenQuestion holds

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LicenceCC BY
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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.