ArticleProceedings of the National Academy of Sciences of the United States of America2022
Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
What it found
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Who cites it
54 citing papers in PubMed, 75 citations in OpenAlex.
- Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.Nature chemical biology · 2026Article
- Preclinical Pharmacokinetic and Pharmacological Profiling of B339, a Novel SARM1 Inhibitor for the Treatment of Vincristine-induced Peripheral Neuropathy.Pharmaceutical research · 2026Article
- Direct activation of SARM1 by dsDNA is not supported by biochemical and cellular evidence.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Nicotinamide Mononucleotide Adenylyltransferase 1 and NADMetabolites · 2026Review
- Peripheral Neuropathy in Metabolic Stress.International journal of molecular sciences · 2026Review
- Boldine inhibits SARM1 NADase Activity and Preserves Axonal Integrity After Nerve Injury.bioRxiv : the preprint server for biology · 2026Article
- Wallerian Degeneration and Nerve Regeneration-A Review of Cellular and Molecular Events.International journal of molecular sciences · 2026Review
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease.Journal of the American Chemical Society · 2026Article
- The rise and fall of SARM1 base-exchange inhibitors.Communications chemistry · 2026Article
- Brain metabolomic profiling reveals ischemia-dominant disruption of metabolic pathways and tissue homeostasis in neonatal hypoxic-ischemic brain injury.Scientific reports · 2026Article
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease ACTMAP.bioRxiv : the preprint server for biology · 2026Article
- Caspase-3 cleaves and activates the NADase SARM1 to promote apoptosis, linking two cell death mechanisms.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Programmed axon degeneration: mechanism, inhibition and therapeutic potential.Nature reviews. Neuroscience · 2026Review
- New mechanistic insight into SARM1 activation: TRIM32-mediated ubiquitination is a key lever that actuates SARM1's catalytic action, leading to axon degeneration and cell death.Frontiers in neural circuits · 2026Article
- Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity.bioRxiv : the preprint server for biology · 2025Article
- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- CySP3-96 Enables Scalable, Streamlined, and Low-Cost Sample Preparation for Cysteine Chemoproteomic Applications.Molecular & cellular proteomics : MCP · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.Molecular neurobiology · 2025Review
- Carnosol, a Rosemary Ingredient Discovered in a Screen for Inhibitors of SARM1-NADAntioxidants (Basel, Switzerland) · 2025Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
The nicotinamide adenine dinucleotide hydrolase (NADase) sterile alpha toll/interleukin receptor motif containing-1 (SARM1) acts as a central executioner of programmed axon death and is a possible therapeutic target for neurodegenerative disorders. While orthosteric inhibitors of SARM1 have been described, this multidomain enzyme is also subject to intricate forms of autoregulation, suggesting the potential for allosteric modes of inhibition. Previous studies have identified multiple cysteine residues that support SARM1 activation and catalysis, but which of these cysteines, if any, might be selectively targetable by electrophilic small molecules remains unknown. Here, we describe the chemical proteomic discovery of a series of tryptoline acrylamides that site-specifically and stereoselectively modify cysteine-311 (C311) in the noncatalytic, autoregulatory armadillo repeat (ARM) domain of SARM1. These covalent compounds inhibit the NADase activity of WT-SARM1, but not C311A or C311S SARM1 mutants, show a high degree of proteome-wide selectivity for SARM1_C311 and stereoselectively block vincristine- and vacor-induced neurite degeneration in primary rodent dorsal root ganglion neurons. Our findings describe selective, covalent inhibitors of SARM1 targeting an allosteric cysteine, pointing to a potentially attractive therapeutic strategy for axon degeneration-dependent forms of neurological disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.