The rise and fall of SARM1 base-exchange inhibitors

@article{lundback2026rise,
  title = {{The rise and fall of SARM1 base-exchange inhibitors}},
  author = {Thomas Lundbäck and Vijay Chandrasekar and Chendi Gu and Hyoungseok Ju and Robyn L. McAdam and Maria Palomero and Kasim Sader and Bradley Peter and Lisa Wissler and Philip Nevin and Edmund Foster and Tanguy Jamier and Pravallika Manjappa and Carina A. Johansson and Jenny Sandmark and Mei Ding and Anette Persson-kry and Sanhita Mitra and Tuğçe Munise Şatır and Bilada Bilican and Mirko Messa and Graham Mathew Fraser and John E. Linley and Helen Plant and Rachel K. Moore and Tina Seifert and Michael Lerche and Carina Raynochek and Ewa Nilsson and Nour K. Majbour and Richard Lucey and Taianá Maia de Oliveira and Qi Wang and Iain P. Chessell and Perla Breccia and Rebecca E. Jarvis},
  journal = {Communications Chemistry},
  year = {2026},
  month = may,
  doi = {10.1038/s42004-026-02074-8},
  url = {https://doi.org/10.1038/s42004-026-02074-8},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - The rise and fall of SARM1 base-exchange inhibitors
AU  - Thomas Lundbäck
AU  - Vijay Chandrasekar
AU  - Chendi Gu
AU  - Hyoungseok Ju
AU  - Robyn L. McAdam
AU  - Maria Palomero
AU  - Kasim Sader
AU  - Bradley Peter
AU  - Lisa Wissler
AU  - Philip Nevin
AU  - Edmund Foster
AU  - Tanguy Jamier
AU  - Pravallika Manjappa
AU  - Carina A. Johansson
AU  - Jenny Sandmark
AU  - Mei Ding
AU  - Anette Persson-kry
AU  - Sanhita Mitra
AU  - Tuğçe Munise Şatır
AU  - Bilada Bilican
AU  - Mirko Messa
AU  - Graham Mathew Fraser
AU  - John E. Linley
AU  - Helen Plant
AU  - Rachel K. Moore
AU  - Tina Seifert
AU  - Michael Lerche
AU  - Carina Raynochek
AU  - Ewa Nilsson
AU  - Nour K. Majbour
AU  - Richard Lucey
AU  - Taianá Maia de Oliveira
AU  - Qi Wang
AU  - Iain P. Chessell
AU  - Perla Breccia
AU  - Rebecca E. Jarvis
PY  - 2026
DA  - 2026/05/19
JO  - Communications Chemistry
DO  - 10.1038/s42004-026-02074-8
UR  - https://doi.org/10.1038/s42004-026-02074-8
AB  - The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades. The sterile alpha and TIR motif containing 1 (SARM1) is a crucial enzyme in axonal degeneration, making it a potential target for treating nervous system diseases. Here, the authors identify and optimize base-exchange inhibitors (BEXi) targeting SARM1, revealing their limitations and highlighting the complexity of SARM1 as a therapeutic target.
SN  - 2399-3669
ER  -