Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome beta 5c Chymotryptic Subunit

摘要

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.