Harrington Paul E, Biswas Kaustav, Malwitz David, Tasker Andrew S, Mohr Christopher, Andrews Kristin L, Dellamaggiore Ken, Kendall Richard, Beckmann Holger, Jaeckel Peter, Materna-Reichelt Silvia, Allen Jennifer R, Lipford J Russell
Departments of Medicinal Chemistry, Molecular Structure, and Oncology, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 93012, United States.
Department of Discovery Technologies, Amgen Research GmbH , Josef-Engert-Str. 11, 93050 Regensburg, Germany.
ACS Med Chem Lett. 2014 Sep 24;6(1):68-72. doi: 10.1021/ml500315b. eCollection 2015 Jan 8.
The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1α endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.
激酶/核酸内切酶肌醇需求酶1（IRE1α）是内质网中未折叠蛋白积累的传感器之一，可触发未折叠蛋白反应（UPR），目前已被作为抗癌靶点进行研究。我们鉴定出了与该酶激酶位点结合的IRE1α核酸内切酶活性的强效变构抑制剂。构效关系（SAR）研究得到了化合物16和18，它们在激酶筛选中具有选择性，并且对重组IRE1α核酸内切酶以及细胞内IRE1α均具有强效抑制作用。获得了与hIRE1α结合的激酶抑制剂（16）的首个X射线晶体结构。针对选择性IRE1α抑制剂对天然肿瘤细胞系（>300种）进行筛选，未显示对细胞活力有任何影响。这些结果表明，在体外，IRE1α活性对于大多数肿瘤细胞系的生存并非必不可少，并且干扰UPR的生存功能可能不是阻断肿瘤发生的有效策略。
