Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration
Year: 2025
Type: article
Abstract: 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.
Source: npj Drug Discovery.
Authors: Rebecca R. Leahey, Martin Weber, Chang Hoon Cho, Seong Kwon Hur, Amber Cramer, Karla Manzanares, Brett Babin, Gladys Boenig, Taylor Kring, Liling Liu, Yusi Cui, Anjani Ganti, John P. Evans, Marika Nespi, Justin Ly, Alicia A. Nugent, Samantha A. Green, Bryan K. Chan, Casper C. Hoogenraad, Anton Delwig, Flora I. Hinz
Institution: Genentech
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,990
Funder: Genentech
OpenAlex ID: W4413487572