PR-924 is a selective inhibitor of tripeptide epoxyketone immunoproteasome subunit LMP-7 (IC50: 22 nM). PR-924 inhibits growth and triggers apoptosis in multiple myeloma (MM) cells. PR-924 has antitumor activities. PR-924 covalently modifies proteasomal N-terminal threonine active sites.

LMP7:22 nM, LMP2:8.2 μM

PR-924 causes BID cleavage and its translocation to mitochondria, as well as cyto-c release BID, a proapoptotic BH-3 family protein, is linked to mitochondrial-mediated apoptotic signaling pathways via cyto-c release. PR-924 (3 μM; 48 hours; MM.1S and MM.1R cells) treatment triggers apoptosis in MM cells. PR-924 (3 μM; 48 hours; MM.1S and MM.1R cells) treatment triggers activation of caspase-3, caspase-8, and caspase-9, and significantly down-regulated the expression of Bcl-2 protein, without altering Bax or MCL-1 protein levels. PR-924 (1-20 μM; 24-72 hours; MM.1S, MM.1R, RPMI-8226, KMS12, LR-5, DOX40, INA-6, OPM1, and OPM2 cells) treatment obviously reduces the viability of all the MM cell lines in a time-and dose-dependent manner (IC 50 range for cell lines: 3-7 μM for 48 h)[1].

PR-924 treatment obviously decreases the shIL-6R levels in SCID-hu model. Treatment of tumor-bearing mice with PR-924 prolongs survival. PR-924 (6 mg/kg; intravenous injection; twice a week; for 21 days; CB-17 SCID-mice) treatment obviously inhibits tumor growth in human plasmacytoma xenografts [1].