Definition

An orally bioavailable inhibitor of the serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 (inositol-requiring enzyme 1 alpha; IRE1), with potential immunoactivating, chemosensitizing and antineoplastic activities. Upon oral administration, IRE1 RNase inhibitor ORIN1001 targets and binds to the RNase domain of IRE1, thereby inhibiting the activity of IRE1. This prevents activation of the IRE1/X-Box Binding Protein 1 (XBP1) pathway, inhibits unfolded protein response (UPR) stress adaptation and prevents the production of pro-tumorigenic factors. This may inhibit tumor growth in which IRE1 is overactivated. In addition, ORIN1001 abrogates the immunosuppressive tumor microenvironment (TME) through cytotoxic T-cell infiltration and depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. IRE1, an endoplasmic reticulum (ER)-localized transmembrane protein containing an ER luminal stress-sensing domain and a cytoplasmic facing RNase domain, acts as a key sensor for the UPR and plays a key role in the response to and resolution of ER stress. IRE1 is involved in both protein phosphorylation and mRNA processing and degradation in response to ER stress-dependent signaling. IRE1 is frequently co-amplified with the MYC oncogene.