Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration.

Rebecca R Leahey¹, Martin Weber¹, Chang Hoon Cho², Seong Kwon Hur¹, Amber Cramer¹, Karla Manzanares³, Brett Babin³, Gladys Boenig⁴, Taylor Kring⁵, Liling Liu⁶, Yusi Cui⁶, Anjani Ganti⁶, John P Evans⁷, Marika Nespi⁵, Justin Ly⁶, Alicia A Nugent², Samantha A Green⁸, Bryan K Chan⁸, Casper C Hoogenraad¹, Anton Delwig⁹, Flora I Hinz¹⁰

¹Department of Neuroscience, Genentech, Inc., South San Francisco, CA, 94080, USA.

²Department of Human Pathobiology and OMNI Reverse Translation, Genentech, Inc., South San Francisco, CA, 94080, USA.

³Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, 94080, USA.

⁴Department of Structural Biology, Genentech, Inc., South San Francisco, CA, 94080, USA.

⁵Department of Pharmaceutics, Genentech, Inc., South San Francisco, CA, 94080, USA.

⁶Department of Drug Metabolism & Pharmacokinetics, Genentech, Inc., South San Francisco, CA, 94080, USA.

⁷Arctoris Ltd, 120E Olympic Avenue, OX14 4SA, Abingdon, United Kingdom.

⁸Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, 94080, USA.

⁹Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, 94080, USA. delwig.anton@gene.com.

¹⁰Department of Neuroscience, Genentech, Inc., South San Francisco, CA, 94080, USA. hinz.flora@gene.com.

PubMed PMC DOI PDF

Abstract

SARM1, an octameric NADase, is a key regulator of axon degeneration and an emerging target in drug discovery to treat a range of neurodegenerative diseases. Recently, a structurally diverse series of adduct-forming, orthosteric SARM1 inhibitors have been discovered. Here, we show that subinhibitory concentrations of these inhibitors, under mildly SARM1 activating conditions, cause sustained SARM1…

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