Dataset Information

Discovery of a Small Molecule Secreted Clustering Enhancer that Improves Moemory in Alzheimer's Disease Mice

ABSTRACT: 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 extraterminal (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 ApoE4-TR:5xFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3XTg AD model, DDL-357 reduced phosho-tau in brain and lead to improvements in mouse performance in the Barnes maze memory 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 assessment of the lead candidate.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jesus Campagna

LAB HEAD: Varghese John

PROVIDER: PXD060173 | Pride | 2026-03-30

REPOSITORIES: Pride

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			Action	DRS
	wc_QE_012324_Whitaker_DDL357-ChronicInVivo_Exp1-F1.raw	Raw
	wc_QE_012324_Whitaker_DDL357-ChronicInVivo_Exp1-F2.raw	Raw
	wc_QE_012324_Whitaker_DDL357-ChronicInVivo_Exp1-F3.raw	Raw
	wc_QE_012324_Whitaker_DDL357-ChronicInVivo_Exp1-F4.raw	Raw
	wc_QE_012324_Whitaker_DDL357-ChronicInVivo_Exp1-F5.raw	Raw

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Publications

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

Cohn Whitaker W Campagna Jesus J Wi Dongwook D Lee Jessica T JT Beniwal Sahiba S Elezi Gazmend G Zhu Chunni C Jagodzinska Barbara B Whitelegge Julian J Damoiseaux Robert R John Varghese V

npj drug discovery 20250502 1

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 p ...[more]

PMID: 40322539

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