pyrazolone and Multiple-Myeloma

Multiple myeloma (MM) cells demonstrate high basal endoplasmic reticulum (ER) stress and are typically exquisitely sensitive to agents such as proteasome inhibitors that activate the unfolded protein response. The flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum oxidoreductin enzyme (Ero1L) catalyzes de-novo disulfide bridge formation of ER resident proteins and contributes to proper protein folding. Here we show that increased Ero1L expression is prognostic of poor outcomes for MM patients relapsing on therapy. We propose that targeting protein folding via inhibition of Ero1L may represent a novel therapeutic strategy for the treatment of MM. In this report we show that treatment of MM cells with EN-460, a known inhibitor of ERO1L, was sufficient to inhibit cell proliferation and induce apoptosis. Furthermore, we show that cell death correlated in part with induction of ER stress. We also show that EN460 inhibited the enzyme activity of Ero1L, with an IC50 of 22.13 μM, consistent with previous reports. However, EN-460 was also found to inhibit other FAD-containing enzymes including MAO-A (IC

Topics: Apoptosis; Binding Sites; Cell Line, Tumor; Endoplasmic Reticulum Stress; Histone Demethylases; Humans; Imidazoles; Kaplan-Meier Estimate; Membrane Glycoproteins; Molecular Docking Simulation; Monoamine Oxidase; Multiple Myeloma; Oxidoreductases; Prognosis; Protein Interaction Domains and Motifs; Pyrazolones; Structure-Activity Relationship