Dataset Information

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

ABSTRACT: Here, we present findings from a drug discovery program aimed at developing small molecules that enhance brain sCLU levels and assessed their impact on AD pathology and cognition. A high-throughput screening campaign identified two classes of epigenetic modulators to increase sCLU levels, and medicinal chemistry efforts led to the development BET inhibitor new chemical entities with enhanced potency, drug-like properties, and oral brain bioavailability. Lead candidate, DDL-357, increased brain sCLU as well as proteins crucial for mitochondrial function, synaptic plasticity, and disease relevant protein aggregate clearance in AD mouse models. DDL-357 reduced p-tau and improved memory, presenting a promising multifaceted therapeutic approach for Alzheimer's treatment.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jesus Campagna

LAB HEAD: Varghese John

PROVIDER: PXD060171 | Pride | 2026-03-30

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	wc_QE_053023_John_Whitaker_DDL357_InVivo_TMT_8Fractions.mzML	Mzml
	wc_QE_053023_John_Whitaker_DDL357_InVivo_TMT_8Fractions.mzTab	Mztab
	wc_QE_053023_John_Whitaker_DDL357_InVivo_TMT_F1.raw	Raw
	wc_QE_053023_John_Whitaker_DDL357_InVivo_TMT_F2.raw	Raw
	wc_QE_053023_John_Whitaker_DDL357_InVivo_TMT_F3.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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