Proteasome inhibitor
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer, especially multiple myeloma.
Present proteasome inhibitors fall into two major categories,inhibitors that are covalently bonded or non-covalently bonded.The former is mostly studies, which form a covalent bond with γ-O of proteasome Thr1 to inactivate proteasome.
Examples
- The first non-peptidic proteasome inhibitor discovered was the natural product lactacystin.[1]
- In 2003, bortezomib(PS-341) was the first proteasome inhibitor to be approved for use in the U.S. It is a potent 20S proteasome inhibitor with Ki of 0.6 nM.
- Disulfiram has been proposed as another proteasome inhibitor.[2][3][4]
- Epigallocatechin-3-gallate has also been proposed.[5]
- Salinosporamide A has started clinical trials for multiple myeloma.
- carfilzomib(PR-171) was approved by the FDA for relapsed and refractory multiple myeloma on 20 July 2012. It is an irreversible proteasome inhibitor with IC50 of <5 nM, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities.
- ONX 0912, CEP-18770, and MLN9708 have also started clinical trials.[6]
- Epoxomicin is a naturally-occurring selective inhibitor.[7]
- MG132 is a synthesized peptide commonly used for in vitro studies with IC50 of 100 nM, and also inhibits calpain with IC50 of 1.2 μM.
- PI-1840 is a reversible and selective chymotrypsin-like (CT-L) inhibitor with IC50 of 27 nM) with little effects on the other two major proteasome proteolytic activities, trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L)[8].
References
- ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ "Current Advances in Novel Proteasome Inhibitor–Based Approaches to the Treatment of Relapsed/Refractory Multiple Myeloma". 2011.
- ^ 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.
{{cite journal}}: Explicit use of et al. in:|first1=(help) - ^ . 5 August http://www.selleckchem.com/pathways_Proteasome.html.
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