A multicatalytic proteolytic complex, the proteasome is responsible for hydrolyzing intracellular proteins and is a common chemotherapeutic target in the treatment of multiple myeloma due to its role in degrading vital cell cycle proteins. Cyclins and tumor suppressors such as p53 accumulate as a result of proteasome inhibition, inducing cell cycle arrest or apoptosis. Multiple myeloma is clinically treated with proteasome inhibitors like carfilzomib, which causes an array of severe side-effects due to lack of proteasomal specificity. The inhibitor proposed in this research combines the potent epoxyketone electrophilic trap from carfilzomib with a rigid macrocyclic moiety derived from the fungal metabolite TMC-95A; the macrocycle contributes to both the potency and selectivity of the inhibitor. The proposed peptidic inhibitor aims to optimize the efficacy of inhibition while increasing selectivity. This study confirmed that the epoxyketone electrophilic trap increases inhibitory potency when compared to amide inhibitors previously synthesized by this research group. Additionally, the formation of essential hydrogen bonds between the oxindole incorporated from TMC-95A and the active site were confirmed by X-ray crystallography. Along with epoxyketone inhibitors, this research introduces the aldoxime electrophilic trap as a potential candidate for proteasomal inhibition.
