Development of tumor-targeting ire-1 inhibitors for b-cell cancer therapy

Andong Shao, Qin Xu, Walker T. Spalek, Christopher F. Cain, Chang Won Kang, Chih Hang Anthony Tang, Juan R. Del Valle, Chih Chi Andrew Hu

Research output: Contribution to journalArticle

Abstract

The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma, and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against cancer cells is highly variable. To design better therapeutic strategies for B-cell cancer, we systematically compared the ability of these compounds to inhibit the RNase activity of IRE-1 in vitro and to suppress the expression of XBP-1s in mouse and human MM cell lines. Tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the most reliable inhibitors for potent suppression of XBP-1s expression in MM cells. The cytotoxicity of B-I09 and D-F07 against MM as well as chronic lymphocytic leukemia and mantle cell lymphoma could be further enhanced by combination with inhibitors of the PI3K/AKT pathway. Because chemical modifications of the salicylaldehyde hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species-sensitive structural cage groups onto these inhibitors to achieve stimuli-responsive activities and improve tumor-targeting efficiency.

Original languageEnglish (US)
Pages (from-to)2432-2444
Number of pages13
JournalMolecular Cancer Therapeutics
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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