Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy.

Brain : a Journal of Neurology
Todd BosanacRaul Krauss

Abstract

Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by SARM1 is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved program of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM...Continue Reading

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Citations

Jul 27, 2021·Frontiers in Molecular Biosciences·Eleanor L HopkinsMichael P Coleman
Aug 18, 2021·Experimental Neurology·Yo SasakiJeffrey Milbrandt
Oct 2, 2021·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Peter Arthur-Farraj, Michael P Coleman
Nov 16, 2021·ELife·Kwang Woo KoAaron DiAntonio

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