IRE-1-Targeting Caged Prodrug with Endoplasmic Reticulum Stress-Inducing and XBP-1S-Inhibiting Activities for Cancer Therapy

Andong Shao, Qin Xu, Chang Won Kang, Christopher F. Cain, Avery C. Lee, Chih Hang Anthony Tang, Juan R. Del Valle, Chih Chi Andrew Hu

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of the IRE-1/XBP-1s pathway supports tumor progression. Here, we report a novel prodrug, TC-D-F07, in which a thiol-reactive dinitrobenzenesulfonyl (Dns) cage was installed onto the C8 hydroxyl of the covalent IRE-1 inhibitor D-F07. The electron-withdrawing Dns group in TC-D-F07 stabilizes the neighboring 1,3-dioxane acetal, allowing for stimulus-mediated control of its inhibitory activity. TC-D-F07 exhibits high sensitivity to intracellular thiols. Because tumor cells exhibit higher concentrations of glutathione and cysteine, treatment with TC-D-F07 results in more sustained levels of D-F07 in transformed versus normal cells. In addition, we show that a dinitrophenyl cysteine adduct resulting from cleavage of the Dns group induces endoplasmic reticulum (ER) stress, causing tumor cells to increase the expression of XBP-1s. The accumulated levels of D-F07 and its gradual decomposition into the active IRE-1 inhibitor eventually deprive tumor cells of XBP-1s, leading to more severe apoptosis than those treated with its uncaged analogue.

Original languageEnglish (US)
Pages (from-to)1059-1067
Number of pages9
JournalMolecular pharmaceutics
Volume19
Issue number4
DOIs
StatePublished - Apr 4 2022

Keywords

  • ATF4
  • ATF6
  • IRE-1
  • PERK
  • cancer
  • endoplasmic reticulum stress
  • unfolded protein response

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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