1. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma.
- Author
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Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, and Koong AC
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Boronic Acids administration & dosage, Bortezomib, Cells, Cultured, Cytotoxins therapeutic use, Dose-Response Relationship, Drug, Humans, Mice, Models, Biological, Multiple Myeloma drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazines administration & dosage, Substrate Specificity drug effects, Sulfonamides administration & dosage, Sulfonamides therapeutic use, Thiophenes administration & dosage, Thiophenes therapeutic use, Xenograft Model Antitumor Assays, Cytotoxins pharmacology, Endoribonucleases antagonists & inhibitors, Multiple Myeloma pathology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Sulfonamides pharmacology, Thiophenes pharmacology
- Abstract
Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.
- Published
- 2011
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