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<p>Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1–cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin–RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4.</p><p></p>

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SINE compounds activate exportin 1 degradation through an allosteric mechanism

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Casey E. Wing,
  • Ho Yee Joyce Fung,
  • Bert Kwanten,
  • Tolga Cagatay,
  • Ashley B. Niesman,
  • Maarten Jacquemyn,
  • Mehdi Gharghabi,
  • Brecht Permentier,
  • Binita Shakya,
  • Rhituparna Nandi,
  • Joseph M. Ready,
  • Trinayan Kashyap,
  • Sharon Shacham,
  • Yosef Landesman,
  • Rosa Lapalombella,
  • Dirk Daelemans,
  • Yuh Min Chook

摘要

Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1–cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin–RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4.