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