Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome β5c Chymotryptic Subunit

We describe our discovery and development
of potent and highly
selective inhibitors of human constitutive proteasome chymotryptic
activity (β5c). Structure–activity relationship studies
of the novel class of inhibitors focused on optimization of N-cap, C-cap, and side chain of the chemophore
asparagine. Compound 32 is the most potent and selective
β5c inhibitor in this study. A docking study provides a structure
rationale for potency and selectivity. Kinetic studies show a reversible
and noncompetitive inhibition mechanism. It enters the cells to engage
the proteasome target, potently and selectively kills multiple myeloma
cells, and does so by synergizing with a β5i-selective inhibitor.