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所需免疫蛋白酶体亚单位抑制谱的抗炎疗效和临床候选药物 KZR-616((2 S,3 R)-N-(( S)-3-(环戊-1-烯-1-基)-1-(( R)-2-甲基环氧乙烷-2-基)-1-氧代丙-2-基)-3-羟基-3-(4-甲氧基苯基)-2-(( S)-2-(2-吗啉乙酰胺基)丙氨酰胺基)丙烯酰胺)。

Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide).

机构信息

Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , California 94080 , United States.

Onyx Pharmaceuticals, an Amgen Subsidiary , South San Francisco , California 94080 , United States.

出版信息

J Med Chem. 2018 Dec 27;61(24):11127-11143. doi: 10.1021/acs.jmedchem.8b01201. Epub 2018 Dec 11.

DOI:10.1021/acs.jmedchem.8b01201
PMID:30380863
Abstract

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.

摘要

选择性免疫蛋白酶体抑制是治疗自身免疫性疾病的一种很有前途的方法，但最佳的蛋白酶活性位点亚基抑制谱尚不清楚。我们在这里揭示了我们设计的基于肽环氧酮的选择性低分子量多肽-7（LMP7）和多催化内肽酶复合物亚基-1（MECL-1）亚基抑制剂。利用这些以及我们之前公开的低分子量多肽-2（LMP2）抑制剂，我们证明了在炎症性疾病模型中，需要双重 LMP7/LMP2 或 LMP7/MECL-1 亚基抑制谱才能有效抑制细胞因子表达和体内疗效。这些以及为提高溶解度而进行的其他研究导致了 KZR-616 的设计和选择，目前正在进行临床试验，用于治疗风湿性疾病。

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Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide).所需免疫蛋白酶体亚单位抑制谱的抗炎疗效和临床候选药物 KZR-616((2 S,3 R)-N-(( S)-3-(环戊-1-烯-1-基)-1-(( R)-2-甲基环氧乙烷-2-基)-1-氧代丙-2-基)-3-羟基-3-(4-甲氧基苯基)-2-(( S)-2-(2-吗啉乙酰胺基)丙氨酰胺基)丙烯酰胺)。
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