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SARM1 TIR with BEXi adduct 17
Structural highlights
FunctionSARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4] Publication Abstract from PubMedThe 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 rise and fall of SARM1 base-exchange inhibitors.,Lundback T, Chandrasekar V, Gu C, Ju H, McAdam R, Palomero M, Sader K, Peter B, Wissler L, Nevin P, Foster E, Jamier T, Manjappa P, Johansson C, Sandmark J, Ding M, Persson-Kry A, Mitra S, Munise Satir T, Bilican B, Messa M, Fraser G, Linley J, Plant H, Moore R, Seifert T, Lerche M, Raynochek C, Nilsson E, Majbour N, Lucey R, Maia de Oliveira T, Wang Q, Chessell I, Breccia P, Jarvis R Commun Chem. 2026 May 19;9(1):183. doi: 10.1038/s42004-026-02074-8. PMID:42156967[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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