2. Academic Validation
  3. 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)

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.
Henry W B Johnson 1,  Eric Lowe 1,  Janet L Anderl 1,  Andrea Fan 1,  Tony Muchamuel 1,  Simeon Bowers 2,  David C Moebius 2,  Christopher Kirk 1,  Dustin L McMinn 1
Affiliations

Affiliations

  • 1 Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , California 94080 , United States.
  • 2 Onyx Pharmaceuticals, an Amgen Subsidiary , South San Francisco , California 94080 , United States.
PMID: 30380863 DOI: 10.1021/acs.jmedchem.8b01201
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.

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