Open AccessIRE-1-Targeting Caged Prodrug with Endoplasmic Reticulum Stress-Inducing and XBP-1S-Inhibiting Activities for Cancer Therapy
Author(s) -
Andong Shao,
Qin Xu,
Chang Won Kang,
Christopher F. Cain,
Avery C. Lee,
Chih-Hang Anthony Tang,
Juan R. Del Valle,
ChihChi Andrew Hu
Publication year - 2022
Publication title -
molecular pharmaceutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 127
eISSN - 1543-8392
pISSN - 1543-8384
DOI - 10.1021/acs.molpharmaceut.1c00639
Subject(s) - endoplasmic reticulum , prodrug , chemistry , glutathione , unfolded protein response , cysteine , apoptosis , intracellular , cancer research , biochemistry , enzyme , medicine
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.