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