The proteasome is an intracellular protein complex that has two major roles: degradation of damaged or mis-folded proteins and targeted removal of proteins involved in cell cycle regulation and gene expression. Cancer cells generally have higher proteasome expression and activity compared to normal cells and are more sensitive to the pro-apoptotic effects of proteasome inhibition. Inhibition of proteasome activity leads to the accumulation of cell cycle inhibitors, ultimately inducing programmed cell death (apoptosis). Although improvement in patient outcome due to proteasome inhibitors is widely accepted, these agents have shown to be efficacious in blood cancer subtypes that preferentially express the immuno-proteasome, while most solid cancers that express the constitutive-proteasome variant remain resistant. Here, we have identified two new proteasome inhibitors (MZ86 and MZ88) that also target the constitutive-proteasome and therefore may provide activity against solid cancers. As such, the principal aim of this study was to evaluate the inhibitory profile of MZ86 and MZ88 against the three catalytic activities of the proteasome, namely tryptic-like, chymotryptic-like and caspase-like, as well as assess their potential as anti-cancer agents.
Cell viability assays of a panel of solid and liquid tumour cell lines (n=8) revealed that MZ86 and MZ88 demonstrate comparable/superior activity compared to current FDA approved proteasome inhibitors Bortezomib and Carfilzomib. Not only did they demonstrate superior inhibition of cellular growth, they also showed less growth inhibition effects on normal cell populations. This implies a wider therapeutic window of our compounds compared with those currently available. Immuno-histochemical analysis of activated caspsase-3 also showed that MZ88 and MZ86 can induce apoptosis in ex vivo treated human breast tissues. We are currently undertaking xenograft studies to test the utility of MZ86 and MZ88 as potential proteasome inhibitors for treatment of solid tumours.