Divergent Allosteric Control of IRE1alpha endoribonuclease using small molecule kinase inhibitors

Abstract

When unfolded proteins get accumulated in the endoplasmic reticulum (ER), signaling pathways called the unfolded protein response (UPR) get turned on in the cell. However under conditions of chronic ER stress, the cell undergoes apoptosis. Key events of this "Terminal UPR" are controlled by IRE1α - an ER bifunctional kinase/endoribonuclease (RNase), which when hyperactivated, oligomerizes causing widespread endonucleolytic decay of ER-localized mRNAs and repressive micro-RNA precursors triggering cell death. Somatic mutations of IRE1α found in human cancers prevent oligomerization and inhibit apoptosis caused by the RNase. Using these results, our lab developed an array of ATP-competitive kinase inhibitors - called KIRAs (Kinase Inhibiting RNase Attenuators) - that inhibit oligomerization of the IRE1α kinase domain and allosterically inhibit the RNase. In this work we have made efforts to expand the existing panel of KIRAs, looking to achieve greater potency and selectivity towards IRE1α and understand IRE1α mechanism of action.