PMID- 30380863
OWN - NLM
STAT- MEDLINE
DCOM- 20191028
LR  - 20210218
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 61
IP  - 24
DP  - 2018 Dec 27
TI  - 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).
PG  - 11127-11143
LID - 10.1021/acs.jmedchem.8b01201 [doi]
AB  - 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.
FAU - Johnson, Henry W B
AU  - Johnson HWB
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - Lowe, Eric
AU  - Lowe E
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - Anderl, Janet L
AU  - Anderl JL
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - Fan, Andrea
AU  - Fan A
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - Muchamuel, Tony
AU  - Muchamuel T
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - Bowers, Simeon
AU  - Bowers S
AD  - Onyx Pharmaceuticals, an Amgen Subsidiary , South San Francisco , California 
      94080 , United States.
FAU - Moebius, David C
AU  - Moebius DC
AD  - Onyx Pharmaceuticals, an Amgen Subsidiary , South San Francisco , California 
      94080 , United States.
FAU - Kirk, Christopher
AU  - Kirk C
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
FAU - McMinn, Dustin L
AU  - McMinn DL
AUID- ORCID: 0000-0002-9584-7524
AD  - Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , 
      California 94080 , United States.
LA  - eng
PT  - Journal Article
DEP - 20181211
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Cytokines)
RN  - 0 (Morpholines)
RN  - 0 (Oligopeptides)
RN  - 0 (PR-957)
RN  - 0 (Proteasome Inhibitors)
RN  - 144416-78-4 (LMP-2 protein)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (LMP7 protein)
RN  - EC 3.4.25.1 (PSMB10 protein, human)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - O4BT6C02M2 (KZR-616)
SB  - IM
MH  - Administration, Intravenous
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/chemistry/pharmacokinetics/*pharmacology
MH  - Arthritis, Experimental/drug therapy
MH  - Arthritis, Rheumatoid/*drug therapy
MH  - Cell Line, Tumor
MH  - Cysteine Endopeptidases/metabolism
MH  - Cytokines/metabolism
MH  - Drug Design
MH  - Female
MH  - Humans
MH  - Mice, Inbred BALB C
MH  - Morpholines/chemistry/pharmacokinetics/*pharmacology
MH  - Oligopeptides/pharmacology
MH  - Proteasome Endopeptidase Complex/immunology/metabolism
MH  - Proteasome Inhibitors/chemistry/pharmacokinetics/*pharmacology
MH  - Structure-Activity Relationship
EDAT- 2018/11/02 06:00
MHDA- 2019/10/29 06:00
CRDT- 2018/11/02 06:00
PHST- 2018/11/02 06:00 [pubmed]
PHST- 2019/10/29 06:00 [medline]
PHST- 2018/11/02 06:00 [entrez]
AID - 10.1021/acs.jmedchem.8b01201 [doi]
PST - ppublish
SO  - J Med Chem. 2018 Dec 27;61(24):11127-11143. doi: 10.1021/acs.jmedchem.8b01201. 
      Epub 2018 Dec 11.