Development of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy.

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 12 Pg. 2432-2444 (12 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 33051362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Hydrogen Peroxide
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• Endoribonucleases

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis
• B-Lymphocytes (drug effects, metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Development (methods)
• Drug Screening Assays, Antitumor (methods)
• Endoribonucleases (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydrogen Peroxide (metabolism)
• Leukemia, B-Cell (drug therapy, etiology, metabolism)
• Lymphoma, B-Cell (drug therapy, etiology, metabolism)
• Mice
• Molecular Structure
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Reactive Oxygen Species (metabolism)