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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.

SUBMITTER: Papandreou I

PROVIDER: S-EPMC3056474 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Papandreou Ioanna I Denko Nicholas C NC Olson Michael M Van Melckebeke Heleen H Lust Sofie S Tam Arvin A Solow-Cordero David E DE Bouley Donna M DM Offner Fritz F Niwa Maho M Koong Albert C AC

Blood 20101116 4

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, ST ...[more]

PMID: 21081713

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