化学
蛋白质亚单位
体内
肽
药理学
生物化学
生物
基因
生物技术
作者
Henry W. B. Johnson,Eric Lowe,Janet L. Anderl,Andrea Fan,Tony Muchamuel,Simeon Bowers,David C. Moebius,Christopher J. Kirk,Dustin L. McMinn
标识
DOI:10.1021/acs.jmedchem.8b01201
摘要
Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.
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