Biological Activity
DSRM-3716 is a potent and selective SARM1 NADase inhibitor (NAD+ hydrolysis IC50 = 75 nM using recombinant SARM1 SAM-TIR construct) th at recapitulates the SARM1-/- phenotype and protects axons from degeneration induced by axotomy (EC50 = 2.1/1.9 μM by fragmentation/NfL release using mouse DRG neurons; 81/88% protection by 1/3 μM DSRM-3716 using human iPSC-derived motor neurons) or mitochondrial dysfunction (3-30 μM DSRM-3716 against 25 μM rotenone-induced injury; mouse DRG neurons). Mechanistically, DSRM-3716 undergoes base exchange with the nicotinamide (NAM) moiety of nicotinamide adenine dinucleotide (NAD+) to yield the bona fide inhibitor 1AD.
