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
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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.
Blood 11/2010; 117(4):1311-4. · 9.90 Impact Factor
