Protein-folding homeostasis is critical for proper cell function. The unfolded protein response (UPR) is a highly regulated signaling pathway that adjusts the capacity of the endoplasmic reticulum (ER) proteostasis network in response to ER stress. Imbalances in ER proteostasis are at the root of a variety of loss- and gain-of-function human diseases. For example, a mutation in a protein can cause loss of ER proteostasis and lead to accumulation of misfolded proteins and aggregates in the ER, as occurs in diseases like alpha 1-antitrypsin (AAT) deficiency-associated liver cancer. Pharmacologic manipulation of UPR signaling to improve ER proteostasis is a promising strategy for therapeutic intervention for both AAT diseases. The UPR comprises three signaling pathways activated downstream of the ER membrane proteins, IRE1, ATF6 and PERK. Recent human genetic, chemical biologic, and <i>in vivo</i> evidence shows that activating the protective IRE1 arm of the UPR has significant promise to ameliorate age-related human diseases. We have identified IRE1 arm-selective activators via cell-based transcriptional reporter high-throughput screening and prioritized compounds based on transcriptional profiling, potency and structural diversity. In collaboration with the Balch Lab, we have tested the impact of the 8 highly selective, non-toxic, IRE1 arm-selective UPR activators on AAT deficiency. We also investigated the neutrophil elastase inhibitory activity of mutant AAT, which is a component of lung disease, and we observed correction of secreted AAT neutrophil elastase inhibitory activity with 6 compounds. These data suggest that small molecule IRE1 arm-selective activators could be ideal for treating AAT lung and liver disease. We have generated analogs of two hit compounds to establish structure-activity relationships and identify new modifications that will allow us to optimize selectivity and potency with respect to rescuing AAT function while minimizing toxicity in cellular models, preparing for making compounds that are functional in humans by oral dosing.

ER protein homeostasis remodeling through pharmacologic IRE1 activation

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.