AN IRE1ALPHA ENDONUCLEASE SPECIFIC INHIBITOR WITH CYTOTOXIC ACTIVITY

摘要

Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematological malignancies, including multiple myeloma (MM). What is disclosed is STF-083010, a novel small molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after ER stress both in vitro and in vivo. Treatment with STF- 083010 showed significant anti-myeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells when compared to other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBPl axis is a promising target for anti-cancer therapy, especially in the context of multiple myeloma.