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)

Henry W B Johnson; Eric Lowe; Janet L Anderl; Andrea Fan; Tony Muchamuel; Simeon Bowers; David C Moebius; Christopher Kirk; Dustin L McMinn

doi:10.1021/acs.jmedchem.8b01201

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.

Authors

Henry W B Johnson¹, Eric Lowe¹, Janet L Anderl¹, Andrea Fan¹, Tony Muchamuel¹, Simeon Bowers², David C Moebius², Christopher Kirk¹, Dustin L McMinn¹

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.

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