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<p>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 activation. This may present a critical liability for orthosteric SARM1 inhibitors in certain patient populations.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

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  • Rebecca R. Leahey,
  • Martin Weber,
  • Chang Hoon Cho,
  • Seong Kwon Hur,
  • Amber Cramer,
  • Karla Manzanares,
  • Brett Babin,
  • Gladys Boenig,
  • Taylor Kring,
  • Liling Liu,
  • Yusi Cui,
  • Anjani Ganti,
  • John P. Evans,
  • Marika Nespi,
  • Justin Ly,
  • Alicia A. Nugent,
  • Samantha A. Green,
  • Bryan K. Chan,
  • Casper C. Hoogenraad,
  • Anton Delwig,
  • Flora I. Hinz

摘要

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 activation. This may present a critical liability for orthosteric SARM1 inhibitors in certain patient populations.