DSRM-3716 is a potent and selective SARM1 NADase inhibitor (NAD+ hydrolysis IC50 = 75 nM using recombinant SARM1 SAM-TIR construct) that 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.
Potent and selective SARM1 NADase inhibitor that protects axons from degeneration induced by axotomy or mitochondrial dysfunction.
Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.
Shi Y, et al.
Molecular Cell, 82, 1643-1659 (2022)
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