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.^[1] Proteasome inhibitors are being studied in the treatment of cancer, and three are approved for use in multiple myeloma.

Examples

• The first non-peptidic proteasome inhibitor discovered was the natural product lactacystin.^[2]
• Disulfiram has been proposed as another proteasome inhibitor.^[3][4][5]
• Epigallocatechin-3-gallate has also been proposed.^[6]
• Marizomib (salinosporamide A) has started clinical trials for multiple myeloma.
• Oprozomib (ONX-0912), delanzomib (CEP-18770) have also started clinical trials.^[7]
• Epoxomicin is a naturally-occurring selective inhibitor.^[8]
• MG132 is a synthesized peptide commonly used for in vitro studies.
• Beta-hydroxy beta-methylbutyrate is a proteasome inhibitor in human skeletal muscle.^[9][10]

Approved medications

• Bortezomib's boron atom binds the catalytic site of the 26S proteasome.^[11] Bortezomib (Velcade) was approved in 2003, the first proteasome inhibitor for use in the U.S.
• 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 July 20, 2012 under the brand name Kyprolis.^[12]
• Ixazomib (trade name Ninlaro) is the first orally-available proteasome inhibitor approved by the FDA on November 20, 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy.^[13]

References

1. Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". PLOS ONE 8 (1): e53263. doi:10.1371/journal.pone.0053263. PMC 3538785. PMID 23308178.
2. Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL. (1995). "Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin". Science 268: 726–31. doi:10.1126/science.7732382. PMID 7732382.
3. Lövborg H, Oberg F, Rickardson L, Gullbo J, Nygren P, Larsson R (March 2006). "Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram". International Journal of Cancer 118 (6): 1577–80. doi:10.1002/ijc.21534. PMID 16206267.
4. Wickström M, Danielsson K, Rickardson L, et al. (January 2007). "Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients". Biochemical Pharmacology 73 (1): 25–33. doi:10.1016/j.bcp.2006.08.016. PMID 17026967.
5. Cvek B, Dvorak Z (August 2008). "The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor?". Drug Discovery Today 13 (15-16): 716–22. doi:10.1016/j.drudis.2008.05.003. PMID 18579431.
6. Osanai K, Landis-Piwowar KR, Dou QP, Chan TH (August 2007). "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". Bioorg. Med. Chem. 15 (15): 5076–82. doi:10.1016/j.bmc.2007.05.041. PMC 2963865. PMID 17544279.
7. "Current Advances in Novel Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma". 2011.
8. Meng, L.; et al. (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". Proc. Natl. Acad. Sci. U.S.A 96: 10403–10408. doi:10.1073/pnas.96.18.10403. PMC 17900. PMID 10468620.
9. 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 (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature on the use of beta-hydroxy-beta-methylbutyrate (HMB) as a nutritional supplement. The ISSN has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. 2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout. 3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. 4. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. 5. Currently, two forms of HMB have been used: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior. 6. HMB has been demonstrated to increase LBM and functionality in elderly, sedentary populations. 7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass (FM). 8. HMB’s mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations. ... 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.
10. Portal S, Eliakim A, Nemet D, Halevy O, Zadik Z (July 2010). "Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices". J. Pediatr. Endocrinol. Metab. 23 (7): 641–50. PMID 20857835. There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). ... Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription.
11. Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838–42. doi:10.1038/sj.leu.2404528. PMID 17268529.
12. "Press Announcements — FDA approves Kyprolis for some patients with multiple myeloma". U.S. Food and Drug Administration. July 20, 2012. Retrieved 24 April 2016.
13. "Press Announcements — FDA approves Ninlaro, new oral medication to treat multiple myeloma". U.S. Food and Drug Administration. Retrieved 24 April 2016.