PMID- 34234005
OWN - NLM
STAT- MEDLINE
DCOM- 20220324
LR  - 20220324
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 49
IP  - 9
DP  - 2021 Sep
TI  - Role of Epoxide Hydrolases and Cytochrome P450s on Metabolism of KZR-616, a 
      First-in-Class Selective Inhibitor of the Immunoproteasome.
PG  - 810-821
LID - 10.1124/dmd.120.000307 [doi]
AB  - KZR-616 is an irreversible tripeptide epoxyketone-based selective inhibitor of 
      the human immunoproteasome. Inhibition of the immunoproteasome results in 
      anti-inflammatory activity in vitro and based on promising therapeutic activity 
      in animal models of rheumatoid arthritis and systemic lupus erythematosus KZR-616 
      is being developed for potential treatment of multiple autoimmune and 
      inflammatory diseases. The presence of a ketoepoxide pharmacophore presents 
      unique challenges in the study of drug metabolism during lead optimization and 
      clinical candidate profiling. This study presents a thorough and systematic in 
      vitro and cell-based enzymatic metabolism and kinetic investigation to identify 
      the major enzymes involved in the metabolism and elimination of KZR-616. Upon 
      exposure to liver microsomes in the absence of NADPH, KZR-616 and its analogs 
      were converted to their inactive diol derivatives with varying degrees of 
      stability. Diol formation was also shown to be the major metabolite in 
      pharmacokinetic studies in monkeys and correlated with in vitro stability results 
      for individual compounds. Further study in intact hepatocytes revealed that 
      KZR-616 metabolism was sensitive to an inhibitor of microsomal epoxide hydrolase 
      (mEH) but not inhibitors of cytochrome P450 (P450) or soluble epoxide hydrolase 
      (sEH). Primary human hepatocytes were determined to be the most robust source of 
      mEH activity for study in vitro. These findings also suggest that the exposure of 
      KZR-616 in vivo is unlikely to be affected by coadministration of inhibitors or 
      inducers of P450 and sEH. SIGNIFICANCE STATEMENT: This work presents a thorough 
      and systematic investigation of metabolism and kinetics of KZR-616 and related 
      analogs in in vitro and cell-based enzymatic systems. Information gained could be 
      useful in assessing novel covalent proteasome inhibitors during lead compound 
      optimization. These studies also demonstrate a robust source in vitro test system 
      that correlated with in vivo pharmacokinetics for KZR-616 and two additional 
      tripeptide epoxyketones.
CI  - Copyright (c) 2021 by The Author(s).
FAU - Fang, Ying
AU  - Fang Y
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Johnson, Henry
AU  - Johnson H
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Anderl, Janet L
AU  - Anderl JL
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Muchamuel, Tony
AU  - Muchamuel T
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - McMinn, Dustin
AU  - McMinn D
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Morisseau, Christophe
AU  - Morisseau C
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Hammock, Bruce D
AU  - Hammock BD
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Kirk, Christopher
AU  - Kirk C
AD  - Kezar Life Sciences, South San Francisco, California.
FAU - Wang, Jinhai
AU  - Wang J
AD  - Kezar Life Sciences, South San Francisco, California jwang@kezarbio.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210707
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Morpholines)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (multicatalytic protease activator)
RN  - 144416-78-4 (LMP-2 protein)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.3.2.9 (EPHX1 protein, human)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (LMP7 protein)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - O4BT6C02M2 (KZR-616)
SB  - IM
MH  - Animals
MH  - Autoimmune Diseases/drug therapy
MH  - Cells, Cultured
MH  - Cysteine Endopeptidases/*immunology/metabolism
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Epoxide Hydrolases/immunology/*metabolism
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Inactivation, Metabolic
MH  - Inflammation/drug therapy
MH  - Macaca fascicularis
MH  - Morpholines/*pharmacology
MH  - Proteasome Endopeptidase Complex/*immunology
MH  - Proteasome Inhibitors/pharmacology
MH  - Proteins/*immunology
EDAT- 2021/07/09 06:00
MHDA- 2022/03/25 06:00
CRDT- 2021/07/08 05:50
PHST- 2020/11/09 00:00 [received]
PHST- 2021/06/24 00:00 [accepted]
PHST- 2021/07/09 06:00 [pubmed]
PHST- 2022/03/25 06:00 [medline]
PHST- 2021/07/08 05:50 [entrez]
AID - dmd.120.000307 [pii]
AID - 10.1124/dmd.120.000307 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2021 Sep;49(9):810-821. doi: 10.1124/dmd.120.000307. Epub 2021 
      Jul 7.