Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces ER Stress and Early Apoptotic Signaling in Multiple Myeloma

Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD activity has been proposed to be preferentially cytotoxic to malignant plasma cells and may overcome proteasome inhibitor resistance, however, the identification of novel inhibitors has been limited. We developed a screening approach to identify ERAD modulators and applied it in the FDA repurposing library. Here we report a novel compound, omaveloxolone (RTA408), inhibits ERAD activity, rapidly induces the unfolded protein response, and leads to rapid induction of caspase 8 mediated apoptotic signaling in MM. Furthermore, we find that unlike proteasome inhibitors (PIs), RTA408 leads to sustained inhibition of ERAD protein degradation without affecting cytosolic protein degradation, which may address key mechanisms of PI resistance. Importantly we find that ERAD inhibition by RTA408 is cytotoxic in malignant plasma cells with PI resistance and has in vivo anti-myeloma activity. Altogether these studies provide pre-clinical evidence for application of a novel ERAD inhibitor in MM and highlight how it can be leveraged to study ER protein regulation in MM.