Structural Tailoring of a Novel Fluorescent IRE-1 RNase Inhibitor to Precisely Control Its Activity

Andong Shao, Chang Won Kang, Chih Hang Anthony Tang, Christopher F. Cain, Qin Xu, Claire M. Phoumyvong, Juan R. Del Valle, Chih Chi Andrew Hu

    Research output: Contribution to journalArticlepeer-review

    10 Scopus citations


    Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde as a 1,3-dioxane acetal led to strong fluorescence emitted by the coumarin chromophore, enabling D-F07 to be tracked inside the cell. We installed a photolabile structural cage on the hydroxy group of D-F07 to generate PC-D-F07. Such a modification significantly stabilized the 1,3-dioxane acetal protecting group, allowing for specific stimulus-mediated control of inhibitory activity. Upon photoactivation, the re-exposed hydroxy group on D-F07 triggered the aldehyde-protecting 1,3-dioxane acetal to slowly decompose, leading to the inhibition of the RNase activity of IRE-1. Our novel findings will also allow for spatiotemporal control of the inhibitory effect of other salicylaldehyde-based compounds currently in development.

    Original languageEnglish (US)
    Pages (from-to)5404-5413
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Issue number11
    StatePublished - Jun 13 2019

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery


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