Proteasome Inhibitor Drugs

Research output: Contribution to journalReview article

Abstract

Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

Original languageEnglish (US)
Pages (from-to)457-476
Number of pages20
JournalAnnual Review of Pharmacology and Toxicology
Volume60
DOIs
StatePublished - Jan 6 2020

Fingerprint

Proteasome Inhibitors
Proteasome Endopeptidase Complex
Pharmaceutical Preparations
Proteins
Mantle-Cell Lymphoma
Protein Subunits
Cell death
United States Food and Drug Administration
Multiple Myeloma
Cell Death
Peptides
Bortezomib
ixazomib
carfilzomib

Keywords

  • bortezomib
  • carfilzomib
  • ixazomib
  • peptide
  • protease
  • ubiquitin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Proteasome Inhibitor Drugs. / Fricker, Lloyd D.

In: Annual Review of Pharmacology and Toxicology, Vol. 60, 06.01.2020, p. 457-476.

Research output: Contribution to journalReview article

@article{a10b4449f3384e8aad4e7a43e963a6e5,
title = "Proteasome Inhibitor Drugs",
abstract = "Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.",
keywords = "bortezomib, carfilzomib, ixazomib, peptide, protease, ubiquitin",
author = "Fricker, {Lloyd D.}",
year = "2020",
month = "1",
day = "6",
doi = "10.1146/annurev-pharmtox-010919-023603",
language = "English (US)",
volume = "60",
pages = "457--476",
journal = "Annual Review of Pharmacology and Toxicology",
issn = "0362-1642",
publisher = "Annual Reviews Inc.",

}

TY - JOUR

T1 - Proteasome Inhibitor Drugs

AU - Fricker, Lloyd D.

PY - 2020/1/6

Y1 - 2020/1/6

N2 - Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

AB - Proteasomes are large, multicatalytic protein complexes that cleave cellular proteins into peptides. There are many distinct forms of proteasomes that differ in catalytically active subunits, regulatory subunits, and associated proteins. Proteasome inhibitors are an important class of drugs for the treatment of multiple myeloma and mantle cell lymphoma, and they are being investigated for other diseases. Bortezomib (Velcade) was the first proteasome inhibitor to be approved by the US Food and Drug Administration. Carfilzomib (Kyprolis) and ixazomib (Ninlaro) have recently been approved, and more drugs are in development. While the primary mechanism of action is inhibition of the proteasome, the downstream events that lead to selective cell death are not entirely clear. Proteasome inhibitors have been found to affect protein turnover but at concentrations that are much higher than those achieved clinically, raising the possibility that some of the effects of proteasome inhibitors are mediated by other mechanisms.

KW - bortezomib

KW - carfilzomib

KW - ixazomib

KW - peptide

KW - protease

KW - ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=85075537519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075537519&partnerID=8YFLogxK

U2 - 10.1146/annurev-pharmtox-010919-023603

DO - 10.1146/annurev-pharmtox-010919-023603

M3 - Review article

C2 - 31479618

AN - SCOPUS:85075537519

VL - 60

SP - 457

EP - 476

JO - Annual Review of Pharmacology and Toxicology

JF - Annual Review of Pharmacology and Toxicology

SN - 0362-1642

ER -