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Proteasome inhibitor

Proteasome inhibitors (INN stem –zomib)[1] are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; three are approved for use in treating multiple myeloma.

Not to be confused with Protease inhibitor.

Mechanism[edit]

Multiple mechanisms are likely to be involved, but proteasome inhibition may prevent degradation of pro-apoptotic factors such as the p53 protein, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. For example, bortezomib causes a rapid and dramatic change in the levels of intracellular peptides.[2]

The first non-peptidic proteasome inhibitor discovered was the natural product .[3]

lactacystin

has been proposed as another proteasome inhibitor.[4][5][6]

Disulfiram

has also been proposed.[7]

Epigallocatechin-3-gallate

has started clinical trials for multiple myeloma.

Marizomib (salinosporamide A)

(ONX-0912), delanzomib (CEP-18770) have also started clinical trials.[8]

Oprozomib

is a naturally occurring selective inhibitor.[9]

Epoxomicin

is a synthesized peptide commonly used for in vitro studies.

MG132

is a proteasome inhibitor in human skeletal muscle[10][11] in vivo.[12]

Beta-hydroxy beta-methylbutyrate

(Velcade) was approved in 2003. This was the first proteasome inhibitor approved for use in the U.S. Its boron atom binds the catalytic site of the 26S proteasome.[13]

Bortezomib

(Kyprolis) was approved by the FDA for relapsed and refractory multiple myeloma in 2012 .[14] It irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome.

Carfilzomib

(Ninlaro) was approved by the FDA in 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy. It is the first orally-available proteasome inhibitor [15]

Ixazomib