Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma
Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma
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DOI：
10.1182/blood-2010-08-303099
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Koong, Albert C.
中科院分区：
文献类型：
--
作者：
Papandreou, Ioanna;Denko, Nicholas C.;Koong, Albert C.
适应性Ire 1-XBP 1通路的激活已在许多实体瘤和血液恶性肿瘤中被鉴定，包括多发性骨髓瘤（MM）。在这里，我们报告的鉴定STF-083010，一种新的小分子抑制剂Ire 1。STF-083010在体外和体内内质网应激后抑制Ire 1核酸内切酶活性，而不影响其激酶活性。用STF-083010处理在模型人MM异种移植物中显示出显著的抗骨髓瘤活性。同样，与其他类似分离的细胞群相比，STF-083010对新鲜分离的人CD 138（+）MM细胞具有优先毒性。这种新的Ire 1抑制剂的鉴定支持了Ire 1-XBP 1轴是抗癌治疗的有希望的靶点的假设，特别是在MM的背景下。2011; 117（4）：1311-1314）
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)