This potent aldehyde-containing tripeptide mimetic (FW = 533.31 g/mol; CAS 863924-64-5) targets the 20 S proteasome (with lowest IC50 values of 58 nm (chymotrypsin-like activity), 53 nm (trypsin-like activity), and 100 nm (caspase-like activity)), forming covalent adducts to active-site threonines. Given its critical role in protein turnover with effect on vital cellular pathways, the ubiquitin-proteasome system advanced to a promising new target in cancer treatment. Cell cycle regulating peptides, pro- and antiapoptotic proteins as well as transcription factors, all necessary for cell survival, are degraded proteasome-dependently. Proteasomal inhibition results in accumulation of myriad of regulatory proteins, leading to confounding signals toward cell cycle progression and induction of apoptosis. In OPM-2, RPMI-8226, U266 multiple myeloma (MM) cell lines and primary MM cells, BSc2118 causes dose-dependent growth inhibitory effects. After 48 hours, dose-dependent apoptosis occurs both in cell lines and primary myeloma cells. G2-M cell cycle arrest occurs after 24 hours, also causing marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-kB activation.
