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

被引：402

作者：

Papandreou, Ioanna ^{[1
]}

Denko, Nicholas C. ^{[1
]}

Olson, Michael ^{[1
]}

Van Melckebeke, Heleen ^{[2
]}

Lust, Sofie ^{[2
]}

Tam, Arvin ^{[3
]}

Solow-Cordero, David E. ^{[4
]}

Bouley, Donna M. ^{[5
]}

Offner, Fritz ^{[2
]}

Niwa, Maho ^{[3
]}

Koong, Albert C. ^{[1
]}

机构：

[1] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA

[2] Ghent Univ Hosp, Dept Hematol, B-9000 Ghent, Belgium

[3] Univ Calif San Diego, Dept Biol Sci, San Diego, CA 92103 USA

[4] Stanford Univ, High Throughput Biosci Ctr, Stanford, CA 94305 USA

[5] Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA

来源：

BLOOD | 2011年 / 117卷 / 04期

基金：

美国国家卫生研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; KINASE/ENDORIBONUCLEASE IRE1P; TUMOR-GROWTH; ACTIVATION; CELLS; REVEALS; PATHWAY;

D O I：

10.1182/blood-2010-08-303099

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 antimy-eloma 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. 2011; 117(4):1311-1314)

引用

页码：1311 / 1314

页数：4

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