TREM2 activation by first-in-class direct small molecule agonists: DEL screening, optimization, biophysical...

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function.
• TREM2 dysfunction is associated with Alzheimer's disease (AD) and other neurodegenerative conditions.
• Direct TREM2 activation presents a potential therapeutic strategy, but small molecule agonists are lacking.

Purpose of the Study:

• To discover and characterize the first small molecule agonists that directly bind and activate TREM2.
• To provide a proof-of-concept for direct pharmacological TREM2 agonism.

Main Methods:

• DNA-encoded library (DEL) screening was employed to identify TREM2 binders.
• Biophysical techniques (TRIC, MST, SPR) validated binding affinity.
• Functional assays assessed Syk phosphorylation, luciferase activity, and microglial phagocytosis.

Main Results:

• A DEL screen yielded a direct TREM2 agonist (4a) with validated binding affinity.
• Compound 4a enhanced microglial phagocytosis and induced Syk phosphorylation.
• Optimized compound 4i showed maintained TREM2 engagement, improved selectivity, and no cytotoxicity.
• Molecular dynamics simulations suggested a novel activation mechanism.

Conclusions:

• The discovery of direct small molecule TREM2 agonists represents a significant advancement.
• These compounds offer a foundation for developing novel therapeutics for AD and neurodegenerative diseases.
• This work validates direct pharmacological targeting of TREM2 for therapeutic intervention.