Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma.

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.
Authors	Ioanna Papandreou, Nicholas C Denko, Michael Olson, Heleen Van Melckebeke, Sofie Lust, Arvin Tam, David E Solow-Cordero, Donna M Bouley, Fritz Offner, Maho Niwa, Albert C Koong
Journal	Blood (Blood) Vol. 117 Issue 4 Pg. 1311-4 (Jan 27 2011) ISSN: 1528-0020 [Electronic] United States
PMID	21081713 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Boronic Acids Cytotoxins Protein Kinase Inhibitors Pyrazines STF 083010 Sulfonamides Thiophenes Bortezomib ERN1 protein, human Protein Serine-Threonine Kinases Endoribonucleases
Topics	Animals Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use) Boronic Acids (administration & dosage) Bortezomib Cells, Cultured Cytotoxins (pharmacology, therapeutic use) Dose-Response Relationship, Drug Endoribonucleases (antagonists & inhibitors) Humans Mice Models, Biological Multiple Myeloma (drug therapy, pathology) Protein Kinase Inhibitors (pharmacology, therapeutic use) Protein Serine-Threonine Kinases (antagonists & inhibitors) Pyrazines (administration & dosage) Substrate Specificity (drug effects) Sulfonamides (administration & dosage, pharmacology, therapeutic use) Thiophenes (administration & dosage, pharmacology, therapeutic use) Xenograft Model Antitumor Assays

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