Pyridine-based small molecule inhibitors of SARM1 alleviate cell death caused by NADase activity

Our investigation has unveiled a series of pyridine-based SARM1 inhibitors, with the lead compound TH-408 exhibiting remarkable potency, achieving an IC50 value of 0.46 mu M. This exceptional inhibitory effect significantly curtailed SARM1-mediated cell death across diverse biological models. This finding highlights the promising therapeutic potential for neurodegenerative disorders by disrupting SARM1 activation and advances our understanding of molecular interventions in these complex disorders, including the regulation of NAD+ metabolism. TH-408 counters toxicity by inhibiting SARM1 activation and NAD+ depletion, offering a promising approach to cell death prevention.