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TitleThe rise and fall of SARM1 base-exchange inhibitors.
Journal, issue, pagesCommun Chem, Vol. 9, Issue 1, Year 2026
Publish dateMay 19, 2026
AuthorsThomas Lundbäck / Vijay Chandrasekar / Chendi Gu / Hyoungseok Ju / Robyn McAdam / Maria Palomero / Kasim Sader / Bradley Peter / Lisa Wissler / Philip Nevin / Edmund Foster / Tanguy Jamier / Pravallika Manjappa / Carina Johansson / Jenny Sandmark / Mei Ding / Anette Persson-Kry / Sanhita Mitra / Tugce Munise Satir / Bilada Bilican / Mirko Messa / Graham Fraser / John Linley / Helen Plant / Rachel Moore / Tina Seifert / Michael Lerche / Carina Raynochek / Ewa Nilsson / Nour Majbour / Richard Lucey / Taiana Maia de Oliveira / Qi Wang / Iain Chessell / Perla Breccia / Rebecca Jarvis /
PubMed AbstractThe 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 ...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.
External linksCommun Chem / PubMed:42156967 / PubMed Central
MethodsEM (single particle)
Resolution2.94 - 3.3 Å
Structure data

56477

9tzw

EMDB-56477, PDB-9tzw:
SARM1 TIR with BEXi adduct 6
Method: EM (single particle) / Resolution: 3.3 Å

56479

9tzy

EMDB-56479, PDB-9tzy:
SARM1 TIR with BEXi adduct 17
Method: EM (single particle) / Resolution: 2.94 Å

Chemicals

PDB-1jzx:
Structural Basis for the Interaction of Antibiotics with the Peptidyl Transferase Center in Eubacteria


PDB Unreleased entry

PDB-1jz0: Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / NAD(+) / SARM1 / TIR / Nad+

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