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.

本研究阐述了人类组成型蛋白酶体糜蛋白酶样活性（β5c）强效且高选择性抑制剂的发现与开发工作。针对这类新型抑制剂，构效关系（Structure–activity relationship）研究聚焦于药效团（chemophore）天冬酰胺的N端帽、C端帽及侧链的优化。本研究中，化合物32是活性最强、选择性最优的β5c抑制剂。分子对接研究为该类抑制剂的活性与选择性提供了结构层面的合理解释。动力学研究表明其作用机制为可逆非竞争性抑制。该化合物可进入细胞结合蛋白酶体靶点，强效且选择性地杀伤多发性骨髓瘤（multiple myeloma）细胞，并通过与β5i选择性抑制剂产生协同效应发挥杀伤作用。