4U6R: Crystal Structure Of Human Ire1 Cytoplasmic Domains In Complex With A Sulfonamide Inhibitor

The kinase/endonuclease inositol requiring enzyme 1 (IRE1alpha), 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 IRE1alpha 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 IRE1alpha endonuclease as well as cellular IRE1alpha. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1alpha was obtained. Screening of native tumor cell lines (>300) against selective IRE1alpha inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1alpha 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.