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 (fi5c). 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 fi5c 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 fi5i-selective inhibitor.

Automated summary

We report the discovery and development of potent and highly selective inhibitors of human constitutive proteasome chymotryptic activity (fi5c). In the optimization of a novel class of inhibitors, structure-activity relationship studies focused on N-cap, C-cap, and side chain of the chemophore asparagine. Compound 32 exhibits the greatest potency and selectivity among the inhibitors tested. Docking studies provide a structural explanation for their potency and selectivity. Kinetic studies reveal a reversible and noncompetitive inhibition mechanism. Compound 32 penetrates cells to engage the proteasome target, potently and selectively killing multiple myeloma cells by synergizing with a fi5i-selective inhibitor.