Proteasome inhibitor

Chemical structure of bortezomib, the first proteasome inhibitor approved for use.

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. 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. Proteasome inhibitors are being studied in the treatment of cancer, and two are approved for use in multiple myeloma.

Examples

• The first non-peptidic proteasome inhibitor discovered was the natural product lactacystin.
• Bortezomib's boron atom binds the catalytic site of the 26S proteasome. Bortezomib was approved in 2003, the first proteasome inhibitor for use in the U.S.
• Disulfiram has been proposed as another proteasome inhibitor.
• Epigallocatechin-3-gallate has also been proposed.
• Salinosporamide A has started clinical trials for multiple myeloma.
• Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. It was approved by the FDA for relapsed and refractory multiple myeloma on 20 July 2012.
• ONX 0912, CEP-18770, and MLN9708 have also started clinical trials.
• Epoxomicin is a naturally-occurring selective inhibitor.
• MG132 is a synthesized peptide commonly used for in vitro studies.
• Ixazomib is in clinical trials as of 2015.