Proteasome inhibitor ONX 0912 is structurally distinct from bortezomib and carfilzomib, inhibits proteasome activity in vitro, and triggers MM cell death. (A-C) Chemical structures of proteasome inhibitors bortezomib, carfilzomib, and ONX 0912. (D) ONX 0912 and carfilzomib inhibit CT-L proteasome activities in human MM cell lines. MM.1S and MM.1R cells were treated with carfilzomib (5nM) and ONX 0912 (3nM) for 48 hours and harvested; cytosolic extracts were then analyzed for CT-L proteasome activities. Results are represented as percent inhibition in proteasome activities in drug-treated versus vehicle control. (E) MM cell lines were treated with or without ONX 0912 at the indicated doses for 48 hours, followed by assessment for cell viability using MTT assays. Data presented are means ± SD (n = 3; P < .05 for all cell lines).