Proteasome inhibitor

File:Carfilzomib structure.svg

The most common hypothesis is that when the proteasome is inhibited, it causes a buildup of proteins in the cell, creating a toxic environment that leads to cell death.{{Cite journal |last=Fricker |first=Lloyd D. |date=2020-01-06 |title=Proteasome Inhibitor Drugs |url=https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-010919-023603 |journal=Annual Review of Pharmacology and Toxicology |language=en |volume=60 |issue= |pages=457–476 |doi=10.1146/annurev-pharmtox-010919-023603 |pmid=31479618 |issn=0362-1642}} The most common proteasome inhibitors block the proteasome-ubiquitin pathway by directly targeting the 20S proteasome itself, rather than inhibiting the ubiquitination of proteins, or the identification of these substrates{{Cite journal |last1=Myung |first1=Jayhyuk |last2=Kim |first2=Kyung Bo |last3=Crews |first3=Craig M. |date=July 2001 |title=The ubiquitin-proteasome pathway and proteasome inhibitors |journal=Medicinal Research Reviews |language=en |volume=21 |issue=4 |pages=245–273 |doi=10.1002/med.1009 |pmid=11410931 |pmc=2556558 |issn=0198-6325}}

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.{{cite journal |vauthors=Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD |title=Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib |journal = PLOS ONE |year = 2013 | issue = 1 | pages = e53263|doi= 10.1371/journal.pone.0053263| pmid=23308178 |volume=8 |pmc=3538785|bibcode=2013PLoSO...853263G |doi-access=free }}

• The first non-peptidic proteasome inhibitor discovered was the natural product lactacystin.{{cite journal |vauthors=Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL |title=Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin |journal=Science |volume=268 |issue=5211 |pages=726–31 |year=1995 |pmid=7732382 |doi=10.1126/science.7732382|bibcode=1995Sci...268..726F |s2cid=37779687 }} File:Ixazomib.svg
• Disulfiram has been proposed as another proteasome inhibitor.{{cite journal |vauthors=Lövborg H, Oberg F, Rickardson L, Gullbo J, Nygren P, Larsson R |title=Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram |journal=International Journal of Cancer |volume=118 |issue=6 |pages=1577–80 |date=March 2006 |pmid=16206267 |doi=10.1002/ijc.21534|doi-access=free }}{{cite journal |vauthors=Wickström M, Danielsson K, Rickardson L, etal |title=Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients |journal=Biochemical Pharmacology |volume=73 |issue=1 |pages=25–33 |date=January 2007 |pmid=17026967 |doi=10.1016/j.bcp.2006.08.016}}{{cite journal |vauthors=Cvek B, Dvorak Z |title=The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? |journal=Drug Discovery Today |volume=13 |issue=15–16 |pages=716–22 |date=August 2008 |pmid=18579431 |doi=10.1016/j.drudis.2008.05.003}}
• Epigallocatechin-3-gallate has also been proposed.{{cite journal |vauthors=Osanai K, Landis-Piwowar KR, Dou QP, Chan TH |title=A para-amino substituent on the D-ring of green tea polyphenol epigallocatechin-3-gallate as a novel proteasome inhibitor and cancer cell apoptosis inducer |journal=Bioorg. Med. Chem. |volume=15 |issue=15 |pages=5076–82 |date=August 2007 |pmid=17544279 |pmc=2963865 |doi=10.1016/j.bmc.2007.05.041 }}
• Marizomib (salinosporamide A) has started clinical trials for multiple myeloma.
• Oprozomib (ONX-0912), delanzomib (CEP-18770) have also started clinical trials.{{cite web |url=http://www.cancernetwork.com/supplements/onc-nov-2011/content/article/10165/1983430 |title=Current Advances in Novel Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma |year=2011 }}
• Epoxomicin is a naturally occurring selective inhibitor.{{cite journal | last1 = Meng | first1 = L.| year = 1999 | title = Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 18| pages = 10403–10408 | pmid = 10468620 | doi=10.1073/pnas.96.18.10403 | pmc=17900| bibcode = 1999PNAS...9610403M|display-authors=etal| doi-access = free}}
• MG132 is a synthesized peptide commonly used for in vitro studies.
• Beta-hydroxy beta-methylbutyrate is a proteasome inhibitor in human skeletal muscle{{cite journal | vauthors = Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J | title = International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) | journal = J. Int. Soc. Sports Nutr. | volume = 10 | issue = 1 | pages = 6 | date = February 2013 | pmid = 23374455 | pmc = 3568064 | doi = 10.1186/1550-2783-10-6 | quote = Skeletal muscle proteolysis is increased in catabolic states such as fasting, immobilization, aging, and disease [77]. HMB has been shown to decrease skeletal muscle protein degradation both in vitro[72,73] and in vivo[78]. ... Indeed, HMB has been shown to decrease proteasome expression [72] and activity [72,78-80] during catabolic states, thus attenuating skeletal muscle protein degradation through the ubiquitin-proteasome pathway. | doi-access = free }}{{cite journal | vauthors = Luckose F, Pandey MC, Radhakrishna K | title = Effects of amino acid derivatives on physical, mental, and physiological activities | journal = Crit. Rev. Food Sci. Nutr. | volume = 55 | issue = 13 | pages = 1793–1807 | date = 2015 | pmid = 24279396 | doi = 10.1080/10408398.2012.708368 | s2cid = 22657268 | quote = HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass.}} in vivo.{{cite journal | vauthors = Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ | title = Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism | journal = J. Physiol. | volume = 591 | issue = 11 | pages = 2911–2923 | date = June 2013 | pmid = 23551944 | pmc = 3690694 | doi = 10.1113/jphysiol.2013.253203 | quote = although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008). }}
• PI31 acts as a 20S proteasome inhibitor used for proteostasis that occurs naturally in the human body.{{Cite journal |last1=Hsu |first1=Hao-Chi |last2=Wang |first2=Jason |last3=Kjellgren |first3=Abbey |last4=Li |first4=Huilin |last5=DeMartino |first5=George N. |date=July 2023 |title=Ηigh-resolution structure of mammalian PI31–20S proteasome complex reveals mechanism of proteasome inhibition |journal=Journal of Biological Chemistry |language=en |volume=299 |issue=7 |pages=104862 |doi=10.1016/j.jbc.2023.104862|doi-access=free |pmid=37236357 |pmc=10319324 }}

• Bortezomib (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.{{cite journal |vauthors=Bonvini P, Zorzi E, Basso G, Rosolen A |title=Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma |journal=Leukemia |volume=21 |issue=4 |pages=838–42 |year=2007 |pmid=17268529 |doi=10.1038/sj.leu.2404528|doi-access=free }}
• Carfilzomib (Kyprolis) was approved by the FDA for relapsed and refractory multiple myeloma in 2012 .{{cite web|title=Press Announcements — FDA approves Kyprolis for some patients with multiple myeloma|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312920.htm|publisher=U.S. Food and Drug Administration|access-date=24 April 2016|date=July 20, 2012}} It irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome.
• Ixazomib (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 {{cite web|title=Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm473771.htm|publisher=U.S. Food and Drug Administration|access-date=24 April 2016|language=en}}

{{reflist|2}}{{Cite journal |last1=Hsu |first1=Hao-Chi |last2=Wang |first2=Jason |last3=Kjellgren |first3=Abbey |last4=Li |first4=Huilin |last5=DeMartino |first5=George N. |date=July 2023 |title=Ηigh-resolution structure of mammalian PI31–20S proteasome complex reveals mechanism of proteasome inhibition |journal=Journal of Biological Chemistry |volume=299 |issue=7 |pages=104862 |doi=10.1016/j.jbc.2023.104862 |doi-access=free |pmid=37236357 |issn=0021-9258|pmc=10319324 }}{{Chemotherapeutic agents}}

*