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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

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 and Chih-Chi Andrew Hu
Andong Shao
1The Wistar Institute, Philadelphia, Pennsylvania.
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Qin Xu
1The Wistar Institute, Philadelphia, Pennsylvania.
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Walker T. Spalek
1The Wistar Institute, Philadelphia, Pennsylvania.
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  • ORCID record for Walker T. Spalek
Christopher F. Cain
2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
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Chang Won Kang
2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
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Chih-Hang Anthony Tang
1The Wistar Institute, Philadelphia, Pennsylvania.
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  • For correspondence: Chu@wistar.org jdelvalle@nd.edu Ctang@wistar.org
Juan R. Del Valle
2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
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  • For correspondence: Chu@wistar.org jdelvalle@nd.edu Ctang@wistar.org
Chih-Chi Andrew Hu
1The Wistar Institute, Philadelphia, Pennsylvania.
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  • For correspondence: Chu@wistar.org jdelvalle@nd.edu Ctang@wistar.org
DOI: 10.1158/1535-7163.MCT-20-0127 Published December 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2432–44

  • Received February 18, 2020.
  • Revision received July 2, 2020.
  • Accepted October 8, 2020.
  • Published first October 13, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (12)
December 2020
Volume 19, Issue 12
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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 and Chih-Chi Andrew Hu
Mol Cancer Ther December 1 2020 (19) (12) 2432-2444; DOI: 10.1158/1535-7163.MCT-20-0127

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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 and Chih-Chi Andrew Hu
Mol Cancer Ther December 1 2020 (19) (12) 2432-2444; DOI: 10.1158/1535-7163.MCT-20-0127
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Molecular Cancer Therapeutics
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