Proteasome inhibitors are drugs that block the action of

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...

s, cellular complexes that break down

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s. They are being studied in the treatment of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

; and three are approved for use in treating

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...

Mechanism

Multiple mechanisms are likely to be involved, but proteasome inhibition may prevent degradation of

pro-apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...

factors such as the p53 protein, permitting activation of

programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...

in neoplastic cells dependent upon suppression of pro-apoptotic pathways. For example,

bortezomib Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...

causes a rapid and dramatic change in the levels of intracellular peptides.

Examples

* The first non-peptidic proteasome inhibitor discovered was the natural product

lactacystin Lactacystin is an organic compound naturally synthesized by bacteria of the genus ''Streptomyces'' first identified as an inducer of neuritogenesis in neuroblastoma cells in 1991.Omura S, Fujimoto T, Otoguro K, Matsuzaki K, Moriguchi R, Tanaka H ...

. *

Disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects o ...

has been proposed as another proteasome inhibitor. * Epigallocatechin-3-gallate has also been proposed. * Marizomib (salinosporamide A) has started clinical trials for

. * Oprozomib (ONX-0912), delanzomib (CEP-18770) have also started clinical trials. * Epoxomicin is a naturally occurring selective inhibitor. *

MG132 MG132 is a potent, reversible, and cell-permeable proteasome inhibitor ( Ki = 4 nM). It belongs to the class of synthetic peptide aldehydes. It reduces the degradation of ubiquitin-conjugated proteins in mammalian cells and permeable strains of ...

is a synthesized peptide commonly used for ''in vitro'' studies. *

Beta-hydroxy beta-methylbutyrate β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, , is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wou ...

is a proteasome inhibitor in human

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

''in vivo''.

Approved medications

Bortezomib Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...

(''Velcade'') was approved in 2003. This was the first proteasome inhibitor approved for use in the U.S. Its

boron Boron is a chemical element with the symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the '' boron group'' it has t ...

atom binds the catalytic site of the 26S proteasome. *

Carfilzomib Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals. The U.S ...

(''Kyprolis'') was approved by the FDA for relapsed and refractory multiple myeloma in 2012 . It irreversibly binds to and inhibits the

chymotrypsin Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duod ...

-like activity of the 20S proteasome. * Ixazomib (''Ninlaro'') was approved by the FDA in 2015 for use in combination with

lenalidomide Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and gen ...

and

dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...

for the treatment of

after at least one prior therapy. It is the first orally-available proteasome inhibitor

References

{{Chemotherapeutic agents *