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)

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

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.

MeSH terms

  • Administration, Intravenous
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Experimental / drug therapy
  • Arthritis, Rheumatoid / drug therapy*
  • Cell Line, Tumor
  • Cysteine Endopeptidases / metabolism
  • Cytokines / metabolism
  • Drug Design
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics
  • Morpholines / pharmacology*
  • Oligopeptides / pharmacology
  • Proteasome Endopeptidase Complex / immunology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacokinetics
  • Proteasome Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Morpholines
  • Oligopeptides
  • PR-957
  • Proteasome Inhibitors
  • LMP-2 protein
  • Cysteine Endopeptidases
  • LMP7 protein
  • PSMB10 protein, human
  • Proteasome Endopeptidase Complex
  • KZR-616