Structure-Based Discovery of Imidazo[4,5-c]pyridine SARM1 Modulators Showing Paradoxical Activation

Area of Science:

• Biochemistry
• Neuroscience
• Medicinal Chemistry

Background:

• Sterile Alpha and TIR Motif Containing 1 (SARM1) is an NAD+ hydrolase enzyme.
• SARM1 is implicated in neurological diseases, particularly axonopathies.
• Inhibition of SARM1 is a therapeutic strategy for neurodegenerative disorders.

Purpose of the Study:

• To discover and characterize novel bicyclic inhibitors of SARM1.
• To investigate the mechanism of inhibition and identify potential liabilities of SARM1 inhibitors.

Main Methods:

• Free-energy perturbation (FEP+) simulations for initial inhibitor identification.
• Hit expansion and optimization of lead compounds.
• X-ray crystallography to determine inhibitor-bound SARM1 structure.
• In vitro and in vivo assays to assess inhibitor efficacy and potential toxicity.

Main Results:

• Discovery of potent and cell-active bicyclic SARM1 inhibitors with slow off-rates.
• Identification of a unique conformational state of W662 in the SARM1 catalytic site induced by inhibitors.
• Characterization of a liability where substrate-based inhibitors may increase neurodegeneration biomarkers at low doses.

Conclusions:

• Novel bicyclic SARM1 inhibitors were identified using FEP+ simulations and subsequent optimization.
• Inhibitor binding induces specific conformational changes in the SARM1 active site.
• A critical liability of substrate-based SARM1 inhibition was identified, necessitating careful dose-response evaluation in vivo.