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

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.