Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma
| Autor: | Michael R. Olson, Ioanna Papandreou, Fritz Offner, Donna M. Bouley, Heleen Van Melckebeke, Nicholas C. Denko, David E. Solow-Cordero, Arvin B. Tam, Maho Niwa, Albert C. Koong, Sofie Lust |
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| Rok vydání: | 2010 |
| Předmět: |
Immunology
Thiophenes Biology Protein Serine-Threonine Kinases Biochemistry Models Biological Substrate Specificity Bortezomib Mice In vivo Antineoplastic Combined Chemotherapy Protocols Endoribonucleases medicine Cytotoxic T cell Animals Humans Kinase activity Cytotoxicity Protein Kinase Inhibitors Cells Cultured Sulfonamides Lymphoid Neoplasia Dose-Response Relationship Drug Cytotoxins Endoplasmic reticulum Biological activity Cell Biology Hematology Molecular biology Boronic Acids Xenograft Model Antitumor Assays In vitro Pyrazines Multiple Myeloma medicine.drug |
| Zdroj: | Blood. 117(4) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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