High-throughput fragment screening identifies a new small molecule scaffold that modulates TREM2 Signaling

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Immunology

Background:

• Fragment-based drug discovery (FBDD) is crucial for identifying novel small molecule scaffolds.
• Triggering receptor expressed on myeloid cells 2 (TREM2) is a key target in neurodegenerative diseases and cancer immunotherapy.
• High-throughput screening (HTS) enables rapid identification of potential drug candidates.

Purpose of the Study:

• To identify novel small molecule modulators of TREM2 using FBDD.
• To characterize the binding affinity and functional activity of identified compounds.
• To explore the potential of these compounds as leads for therapeutic development.

Main Methods:

• Utilized a fragment library of 3200 compounds screened via temperature-related intensity change (TRIC)-based HTS.
• Performed dose-dependent assays, "SAR by catalog" studies, thermal shift assay (TSA), and selectivity profiling.
• Conducted in vitro TREM2 activation assays, SYK/DAP12 phosphorylation studies, and microglial phagocytosis assays.
• Employed in silico analysis, including molecular dynamics (MD) simulations, to assess compound-target interactions.

Main Results:

• Identified novel scaffolds binding to TREM2.
• Derivative 6B10-9 emerged as a lead compound with moderate TREM2 binding affinity (K_D = 68.3 μM).
• 6B10-9 demonstrated significant effects on TREM2-dependent SYK/DAP12 phosphorylation and microglial phagocytosis.
• In silico analysis confirmed stable complex formation between 6B10-9 and TREM2.

Conclusions:

• 6B10-9 is a promising lead compound for developing small molecule-based TREM2 modulators.
• The identified compounds show potential for therapeutic applications in TREM2-associated diseases.
• This study highlights the efficacy of TRIC-based HTS in FBDD for identifying novel drug leads.