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 and implicated in neurodegenerative diseases like Alzheimer's.
• Activating TREM2 presents a potential therapeutic strategy, but direct small molecule agonists have been lacking.

Purpose of the Study:

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

Main Methods:

• DNA-encoded library (DEL) screening was employed to identify TREM2-binding small molecules.
• Biophysical techniques (TRIC, MST, SPR) validated binding affinity.
• Cell-based assays assessed Syk phosphorylation and microglial phagocytosis.
• Molecular dynamics simulations elucidated the binding mechanism.

Main Results:

• The DEL screen yielded a hit compound (4a) with validated TREM2 binding.
• Compound 4a induced TREM2 signaling (Syk phosphorylation) and enhanced microglial phagocytosis.
• Optimized compound (4i) maintained TREM2 engagement with improved selectivity and no cytotoxicity.
• Molecular simulations suggested a novel TREM2 activation mechanism via stabilization of a transient pocket.

Conclusions:

• This study reports the discovery of the first small molecule agonists directly targeting TREM2.
• These findings provide a foundation for developing novel therapeutics for Alzheimer's disease and related neurodegenerative conditions.
• Direct pharmacological TREM2 agonism is demonstrated as a viable therapeutic strategy.