Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration

SARM1, an octameric NADase, is a key regulator of axon degeneration and an emerging target in drug discovery to treat a range of neurodegenerative diseases. Recently, a structurally diverse series of adduct-forming, orthosteric SARM1 inhibitors have been discovered. Here, we show that subinhibitory concentrations of these inhibitors, under mildly SARM1 activating conditions, cause sustained SARM1 activation. This may present a critical liability for orthosteric SARM1 inhibitors in certain patient populations.