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.

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.