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

I Papandreou, NC Denko, M Olson… - Blood, The Journal …, 2011 - ashpublications.org
I Papandreou, NC Denko, M Olson, H Van Melckebeke, S Lust, A Tam, DE Solow-Cordero
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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