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.
Authors
- Seong Kwon Hur
- Samantha A. Green
- Alicia Nugent
- Justin Q. Ly (ORCID: https://orcid.org/0000-0001-5242-7282)
- Bryan Chan (ORCID: https://orcid.org/0000-0002-1086-4596)
- John P. Evans (ORCID: https://orcid.org/0000-0001-8644-5825)
- Chang Hoon Cho (ORCID: https://orcid.org/0000-0002-4870-8767)
- Casper C. Hoogenraad (ORCID: https://orcid.org/0000-0002-2666-0758)
- Anton Delwig
- Rebecca Leahey
- Martin Weber (ORCID: https://orcid.org/0000-0001-5039-5010)
- Liling Liu (ORCID: https://orcid.org/0000-0003-1626-8880)
- Marika Nespi
- Amber Cramer
- Karla Manzanares
- Brett Babin
- Taylor Kring
- Anjani Ganti
- Flora I. Hinz
- Gladys Boenig
- Yusi Cui
Institutions
- Gene Therapy Laboratory (FR)
- Joint Center for Structural Genomics (US)
- Sunesis (United States) (US)
Publication Details
- Journal
- npj Drug Discovery.
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1038/s44386-025-00023-4
- Citations
- 4
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Genentech