4μ8C

The inositol-requiring enzyme 1α (IRE1α) is a serine-threonine kinase that plays crucial roles in activating the unfolded protein response. Studies suggest that IRE1α is activated during thymic T cell development and in effector CD8+ T cells. 4μ8C is a potent and selective IRE1 Rnase inhibitor.

In vitro: 4μ8c is a potent and non-toxic inhibitor of IRE1 RNase activation in response to both hypoxia and other ER stress-inducing agents. This compound effectively inhibited IRE1 induced activation of the downstream target genes in both HCT116 colorectal cancer and KP4 pancreatic cancer cell lines under hypoxia. However, despite potent inhibition of IRE1 activation and the, 4μ8c had no effect on cell proliferation or clonogenic survival of HCT116 and KP4 cells during exposure to hypoxia or anoxia. Similarly, 4μ8c inhibition of IRE1 did not sensitize cells to other ER stress inducing agents [1].

In vivo: 4μ8C has not been tested in vivo, probably because of its unfavourable pharmacokinetics.

Clinical trial: Up to now, 4μ8C is still in the preclinical development stage.

IRE1α是一种丝氨酸/苏氨酸激酶，在激活未折叠蛋白反应中发挥关键作用。研究表明，在胸腺T细胞发育和效应CD8+ T细胞中，IRE1α被激活。4μ8C是一种有效选择性的IRE1 Rnase抑制剂。

体外：4μ8c是IRE1 RNase在缺氧和其他ER胁迫诱导剂作用下的有效无毒抑制剂。该化合物有效抑制了在缺氧条件下HCT116结直肠癌和KP4胰腺癌细胞系中IRE1诱导的下游靶基因的激活。然而，尽管4μ8c有效抑制IRE1激活，但其对HCT116和KP4细胞在缺氧或无氧条件下的细胞增殖或克隆存活率没有影响。同样，4μ8c对IRE1的抑制也没有使细胞对其他ER胁迫诱导剂产生敏感性[1]。

体内：由于其不利的药代动力学，4μ8C尚未在体内进行测试。

临床试验：目前，4μ8C仍处于临床前开发阶段。

Reference:
[1] Dan Cojocari, Ravi Vellanki, Brandon Sit, Marianne Koritzinsky, and Bradly G.  Wouters. IRE1 and PERK as targets of cellular adaptation and survival to hypoxia. Mol Cancer Ther 2013;12(11 Suppl):C284.
[2] Hetz C, Chevet E, Harding HP.  Targeting the unfolded protein response in disease. Nat Rev Drug Discov. 2013 Sep;12(9):703-19.