IRE1

IRE1 inhibitors block inositol-requiring enzyme 1 (IRE1), a sensor of endoplasmic reticulum stress. In 1993, yeast IRE1 was identified as a transmembrane protein kinase required to induce genes for endoplasmic reticulum resident proteins. The enzyme couples a cytosolic kinase domain to an endoribonuclease (RNase) domain. Studies in 2001 and 2002 showed that IRE1 splices X-box binding protein 1 (XBP1) mRNA, producing an active transcription factor of the unfolded protein response. 4μ8C, STF-083010 and MKC8866 inhibit the RNase activity of IRE1α. KIRA6 and Kira8 bind the kinase site and suppress RNase activity allosterically, whereas APY29 is an ATP-competitive ligand of the kinase domain.