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

Endoplasmic reticulum-associated degradation (ERAD) is essential for maintaining protein homeostasis, yet its regulatory mechanisms remain poorly understood. A major challenge in studying ERAD is the lack of specific inhibitors targeting the ERAD complex. To address this, we conducted a cell-based high-throughput screen using the FDA-repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates. Beyond its utility in identifying ERAD substrates, RTA408 exhibits strong cytotoxic effects in multiple myeloma (MM), an incurable plasma cell malignancy. RTA408 inhibits ERAD activity and rapidly induces apoptotic signaling via caspase 8 and the death-inducing signaling complex (DISC). Notably, RTA408 is cytotoxic to malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish ERAD inhibitors as valuable tools for dissecting ERAD regulation while also highlighting their potential as therapeutic agents for MM. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/646787v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@96254aorg.highwire.dtl.DTLVardef@16a3f6dorg.highwire.dtl.DTLVardef@6a1503org.highwire.dtl.DTLVardef@897c45_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe developed a cell-based screening approach to identify novel modulators of endoplasmic reticulum associated degradation (ERAD), with implications in studying ERAD biology and targeting plasma cell neoplasms. C_LIO_LIScreening of the FDA-repurposing library identified Omaveloxolone (RTA408) as an inhibitor of luminal and membrane ERAD substrate degradation, which can be leveraged to identify ERAD substrates. C_LIO_LImaveloxolone treatment rapidly induces the unfolded protein response and apoptosis that is dependent on caspase 8 and death-inducing signaling complex (DISC) in multiple myeloma cells. C_LIO_LImaveloxolone exhibits cytotoxic effects against multiple myeloma cells in vitro and in vivo and induces apoptosis in primary plasma cells from patients with relapsed/refractory myeloma C_LI