Abstract
The proteasome continues to be an attractive target for cancer drug discovery and was validated as such by the successful development of bortezomib. Despite its remarkable efficacy, concerns regarding side effects and drug resistance limit the widespread application of bortezomib. Thus, there has been a heightened interest in the development of a new class of proteasome inhibitors. In this chapter, we discuss recent efforts towards the development of proteasome inhibitors. In addition, we discuss a novel class of compounds targeting an alternative proteasome, the immunoproteasome.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adams, J. (2002). Development of the proteasome inhibitor PS-341. Oncologist 7, 9–16.
Adams, J., Behnke, M., Chen, S., Cruickshank, A.A., Dick, L.R., Grenier, L., Klunder, J.M., Ma, Y.T., Plamondon, L., and Stein, R.L. (1998). Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 8, 333–338.
Berkers, C.R., Verdoes, M., Lichtman, E., Fiebiger, E., Kessler, B.M., Anderson, K.C., Ploegh, H.L., Ovaa, H., and Galardy, P.J. (2005). Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nat Methods 2, 357–362.
Berkers, C.R., van Leeuwen, F.W., Groothuis, T.A., Peperzak, V., van Tilburg, E.W., Borst, J., Neefjes, J.J., and Ovaa, H. (2007). Profiling proteasome activity in tissue with fluorescent probes. Mol Pharm 4, 739–748.
Blum, G., Mullins, S.R., Keren, K., Fonovic, M., Jedeszko, C., Rice, M.J., Sloane, B.F., and Bogyo, M. (2005). Dynamic imaging of protease activity with fluorescently quenched activity-based probes. Nat Chem Biol 1, 203–209.
Bogyo, M., McMaster, J.S., Gaczynska, M., Tortorella, D., Goldberg, A.L., and Ploegh, H. (1997). Covalent modification of the active site threonine of proteasomal beta subunits and the Escherichia coli homolog HslV by a new class of inhibitors. Proc Natl Acad Sci U S A 94, 6629–6634.
Bogyo, M., Shin, S., McMaster, J.S., and Ploegh, H.L. (1998). Substrate binding and sequence preference of the proteasome revealed by active-site-directed affinity probes. Chem Biol 5, 307–320.
Borissenko, L., and Groll, M. (2007). 20S proteasome and its inhibitors: crystallographic knowledge for drug development. Chem Rev 107, 687–717.
Brannigan, J.A., Dodson, G., Duggleby, H.J., Moody, P.C., Smith, J.L., Tomchick, D.R., and Murzin, A.G. (1995). A protein catalytic framework with an N-terminal nucleophile is capable of self-activation. Nature 378, 416–419.
Bromme, D., Klaus, J.L., Okamoto, K., Rasnick, D., and Palmer, J.T. (1996). Peptidyl vinyl sulfones: a new class of potent and selective cysteine protease inhibitors. Biochem J 315, 85–89.
Cardozo, C. (1993). Catalytic components of the bovine pituitary multicatalytic proteinase complex (proteasome). Enzyme Protein 47, 296–305.
Chauhan, D., Li, G., Podar, K., Hideshima, T., Mitsiades, C., Schlossman, R., Munshi, N., Richardson, P., Cotter, F.E., and Anderson, K.C. (2004). Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells. Blood 104, 2458–2466.
Chauhan, D., Hideshima, T., and Anderson, K.C. (2006). A novel proteasome inhibitor NPI-0052 as an anticancer therapy. Br J Cancer 95, 961–965.
Chen, D., Daniel, K.G., Kuhn, D.J., Kazi, A., Bhuiyan, M., Li, L., Wang, Z., Wan, S.B., Lam, W.H., Chan, T.H., and Dou, Q.P. (2004). Green tea and tea polyphenols in cancer prevention. Front Biosci 9, 2618–2631.
Chen, D., Daniel, K.G., Chen, M.S., Kuhn, D.J., Landis-Piwowar, K.R., and Dou, Q.P. (2005). Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69, 1421–1432.
Ciechanover, A., Orian, A., and Schwartz, A.L. (2000). Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22, 442–451.
Demo, S.D., Kirk, C.J., Aujay, M.A., Buchholz, T.J., Dajee, M., Ho, M.N., Jiang, J., Laidig, G.J., Lewis, E.R., Parlati, F., Shenk, K.D., Smyth, M.S., Sun, C.M., Vallone, M.K., Woo, T.M., Molineaux, C.J., and Bennett, M.K. (2007). Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67, 6383–6391.
Dick, L.R., Cruikshank, A.A., Grenier, L., Melandri, F.D., Nunes, S.L., and Stein, R.L. (1996). Mechanistic studies on the inactivation of the proteasome by lactacystin: a central role for clasto-lactacystin beta-lactone. J Biol Chem 271, 7273–7276.
Dick, L.R., Cruikshank, A.A., Destree, A.T., Grenier, L., McCormack, T.A., Melandri, F.D., Nunes, S.L., Palombella, V.J., Parent, L.A., Plamondon, L., and Stein, R.L. (1997). Mechanistic studies on the inactivation of the proteasome by lactacystin in cultured cells. J Biol Chem 272, 182–188.
Elofsson, M., Splittgerber, U., Myung, J., Mohan, R., and Crews, C.M. (1999). Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide alpha′,beta′-epoxyketones. Chem Biol 6, 811–822.
Feling, R.H., Buchanan, G.O., Mincer, T.J., Kauffman, C.A., Jensen, P.R., and Fenical, W. (2003). Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42, 355–357.
Fenteany, G., Standaert, R.F., Lane, W.S., Choi, S., Corey, E.J., and Schreiber, S.L. (1995). Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268, 726–731.
Fevig, J.M., Buriak, J., Jr., Cacciola, J., Alexander, R.S., Kettner, C.A., Knabb, R.M., Pruitt, J.R., Weber, P.C., and Wexler, R.R. (1998). Rational design of boropeptide thrombin inhibitors: beta, beta-dialkyl- phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile. Bioorg Med Chem Lett 8, 301–306.
Figueiredo-Pereira, M.E., Berg, K.A., and Wilk, S. (1994). A new inhibitor of the chymotrypsin-like activity of the multicatalytic proteinase complex (20S proteasome) induces accumulation of ubiquitin- protein conjugates in a neuronal cell. J Neurochem 63, 1578–1581.
Figueiredo-Pereira, M.E., Chen, W.E., Li, J., and Johdo, O. (1996). The antitumor drug aclacinomycin A, which inhibits the degradation of ubiquitinated proteins, shows selectivity for the chymotrypsin-like activity of the bovine pituitary 20S proteasome. J Biol Chem 271, 16455–16459.
Fitzpatrick, L.R., Khare, V., Small, J.S., and Koltun, W.A. (2006). Dextran sulfate sodium-induced colitis is associated with enhanced low molecular mass polypeptide 2 (LMP2) expression and is attenuated in LMP2 knockout mice. Dig Dis Sci 51, 1269–1276.
Fitzpatrick, L.R., Small, J.S., Poritz, L.S., McKenna, K.J., and Koltun, W.A. (2007). Enhanced intestinal expression of the proteasome subunit low molecular mass polypeptide 2 in patients with inflammatory bowel disease. Dis Colon Rectum 50, 337–348; discussion 348–350.
Groll, M., Ditzel, L., Lowe, J., Stock, D., Bochtler, M., Bartunik, H.D., and Huber, R. (1997). Structure of 20S proteasome from yeast at 2.4 A resolution. Nature 386, 463–471.
Groll, M., Kim, K.B., Kairies, N., Huber, R., and Crews, C.M. (2000). Crystal structure of epoxomicin:20S proteasome reveals a molecular basis for selectivity of α′,β′-epoxyketone proteasome inhibitors. J Am Chem Soc 122, 1237–1238.
Groll, M., Koguchi, Y., Huber, R., and Kohno, J. (2001). Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor. J Mol Biol 311, 543–548.
Groll, M., Huber, R., and Potts, B.C. (2006). Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J Am Chem Soc 128, 5136–5141.
Hanada, M., Sugawara, K., Kaneta, K., Toda, S., Nishiyama, Y., Tomita, K., Yamamoto, H., Konishi, M., and Oki, T. (1992). Epoxomicin, a new antitumor agent of microbial origin. J Antibiot (Tokyo) 45, 1746–1752.
Harvey, A.L. (1999). Medicines from nature: are natural products still relevant to drug discovery? Trends Pharmacol Sci 20, 196–198.
Hershko, A., and Ciechanover, A. (1998). The ubiquitin system. Annu Rev Biochem 67, 425–479.
Ho, Y.K., Bargagna-Mohan, P., Mohan, R., and Kim, K.B. (2007). LMP2-specific inhibitors: Novel chemical genetic tools for proteasome biology. Chem Biol 14, 419–430.
Joazeiro, C.A., Anderson, K.C., and Hunter, T. (2006). Proteasome inhibitor drugs on the rise. Cancer Res 66, 7840–7842.
Karin, M., and Ben-Neriah, Y. (2000). Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18, 621–663.
Kazi, A., Daniel, K.G., Smith, D.M., Kumar, N.B., and Dou, Q.P. (2003). Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 66, 965–976.
Kessler, B.M., Tortorella, D., Altun, M., Kisselev, A.F., Fiebiger, E., Hekking, B.G., Ploegh, H.L., and Overkleeft, H.S. (2001). Extended peptide-based inhibitors efficiently target the proteasome and reveal overlapping specificities of the catalytic beta-subunits. Chem Biol 8, 913–929.
Kim, K.B., and Crews, C.M. (2003). Natural product and synthetic proteasome inhibitors. In Cancer Drug Discovery and Development: Proteasome Inhibitors in Cancer Therapy, J. Adams, ed. (Totowa, NJ: Humana Press Inc.), pp. 47–63.
King, R.W., Deshaies, R.J., Peters, J.M., and Kirschner, M.W. (1996). How proteolysis drives the cell cycle. Science 274, 1652–1659.
Kisselev, A.F., and Goldberg, A.L. (2001). Proteasome inhibitors: from research tools to drug candidates. Chem Biol 8, 739–758.
Kisselev, A.F., Callard, A., and Goldberg, A.L. (2006). Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J Biol Chem 281, 8582–8590.
Kloetzel, P.M. (2001). Antigen processing by the proteasome. Nat Rev Mol Cell Biol 2, 179–187.
Koguchi, Y., Kohno, J., Nishio, M., Takahashi, K., Okuda, T., Ohnuki, T., and Komatsubara, S. (2000). TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities. J Antibiot (Tokyo) 53, 105–109.
Koguchi, Y., Kohno, J., Suzuki, S., Nishio, M., Takahashi, K., Ohnuki, T., and Komatsubara, S. (2000). TMC-86A, B and TMC-96, new proteasome inhibitors from Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094. II. Physico-chemical properties and structure determination. J Antibiot (Tokyo) 53, 63–65.
Kohno, J., Koguchi, Y., Nishio, M., Nakao, K., Kuroda, M., Shimizu, R., Ohnuki, T., and Komatsubara, S. (2000). Structures of TMC-95A-D: novel proteasome inhibitors from Apiospora montagnei sacc. TC 1093. J Org Chem 65, 990–995.
Loidl, G., Groll, M., Musiol, H.J., Huber, R., and Moroder, L. (1999a). Bivalency as a principle for proteasome inhibition. Proc Natl Acad Sci U S A 96, 5418–5422.
Loidl, G., Groll, M., Musiol, H.J., Ditzel, L., Huber, R., and Moroder, L. (1999b). Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes. Chem Biol 6, 197–204.
Loidl, G., Musiol, H.J., Groll, M., Huber, R., and Moroder, L. (2000). Synthesis of bivalent inhibitors of eucaryotic proteasomes. J Pept Sci 6, 36–46.
Lowe, J., Stock, D., Jap, B., Zwickl, P., Baumeister, W., and Huber, R. (1995). Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution. Science 268, 533–539.
Lu, C., Gallegos, R., Li, P., Xia, C.Q., Pusalkar, S., Uttamsingh, V., Nix, D., Miwa, G.T., and Gan, L.S. (2006). Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes. Drug Metab Dispos 34, 702–708.
Meng, L., Kwok, B.H., Sin, N., and Crews, C.M. (1999a). Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Res 59, 2798–2801.
Meng, L., Mohan, R., Kwok, B.H., Elofsson, M., Sin, N., and Crews, C.M. (1999b). Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A 96, 10403–10408.
Myung, J., Kim, K.B., and Crews, C.M. (2001a). The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev 21, 245–273.
Myung, J., Kim, K.B., Lindsten, K., Dantuma, N.P., and Crews, C.M. (2001b). Lack of proteasome active site allostery as revealed by subunit-specific inhibitors. Mol Cell 7, 411–420.
Nam, S., Smith, D.M., and Dou, Q.P. (2001). Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem 276, 13322–13330.
Nazif, T., and Bogyo, M. (2001). Global analysis of proteasomal substrate specificity using positional-scanning libraries of covalent inhibitors. Proc Natl Acad Sci U S A 98, 2967–2972.
Oinonen, C., and Rouvinen, J. (2000). Structural comparison of Ntn-hydrolases. Protein Sci 9, 2329–2337.
Omura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., and Sasaki, Y. (1991). Lactacystin, a novel microbial metabolite, induces neuritogenesis of 000neuroblastoma cells. J Antibiot (Tokyo) 44, 113–116.
Orlowski, M. (1993). The multicatalytic proteinase complex (proteasome) and intracellular protein degradation: diverse functions of an intracellular particle. J Lab Clin Med 121, 187–189.
Orlowski, R., and Orlowski, M. (2006). Potent and specific immunoproteasome inhibitors United States Patent Application 20060241056.
Orlowski, R.Z. (2005). The ubiquitin proteasome pathway from bench to bedside. Hematology (Am Soc Hematol Educ Program), 220–225.
Ostrowska, H., Wojcik, C., Omura, S., and Worowski, K. (1997). Lactacystin, a specific inhibitor of the proteasome, inhibits human platelet lysosomal cathepsin A-like enzyme. Biochem Biophys Res Commun 234, 729–732.
Ostrowska, H., Wojcik, C., Wilk, S., Omura, S., Kozlowski, L., Stoklosa, T., Worowski, K., and Radziwon, P. (2000). Separation of cathepsin A-like enzyme and the proteasome: evidence that lactacystin/beta-lactone is not a specific inhibitor of the proteasome. Int J Biochem Cell Biol 32, 747–757.
Palmer, J.T., Rasnick, D., Klaus, J.L., and Bromme, D. (1995). Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem 38, 3193–3196.
Rock, K.L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D., and Goldberg, A.L.(1994). Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771.
Ruiz, S., Krupnik, Y., Keating, M., Chandra, J., Palladino, M., and McConkey, D. (2006). The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol Cancer Ther 5, 1836–1843.
Sadaghiani, A.M., Verhelst, S.H., and Bogyo, M. (2007). Tagging and detection strategies for activity-based proteomics. Curr Opin Chem Biol 11, 20–28.
Sekizawa, R., Momose, I., Kinoshita, N., Naganawa, H., Hamada, M., Muraoka, Y., Iinuma, H., and Takeuchi, T. (2001). Isolation and structural determination of phepropeptins A, B, C, and D, new proteasome inhibitors, produced by Streptomyces sp. J Antibiot (Tokyo) 54, 874–881.
Sin, N., Meng, L., Auth, H., and Crews, C.M. (1998). Eponemycin analogues: syntheses and use as probes of angiogenesis. Bioorg Med Chem 6, 1209–1217.
Sin, N., Kim, K.B., Elofsson, M., Meng, L., Auth, H., Kwok, B.H., and Crews, C.M. (1999). Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorg Med Chem Lett 9, 2283–2288.
Spaltenstein, A., Leban, J.J., Huang, J.J., Reinhardt, K.R., Viveros, O.H.S.J., and Crouch, R. (1996). Design and synthesis of novel protease inhibitors. Tripeptide α′,β′-epoxyketones as nanomolar inactivators of proteasome. Tetrahedron Lett. 37, 1343–1346.
Sugawara, K., Hatori, M., Nishiyama, Y., Tomita, K., Kamei, H., Konishi, M., and Oki, T. (1990). Eponemycin, a new antibiotic active against B16 melanoma. I. Production, isolation, structure and biological activity. J Antibiot (Tokyo) 43, 8–18.
Tan, G., Gyllenhaal, C., and Soejarto, D.D. (2006). Biodiversity as a source of anticancer drugs. Curr Drug Targets 7, 265–277.
van Swieten, P.F., Samuel, E., Hernandez, R.O., van den Nieuwendijk, A.M., Leeuwenburgh, M.A., van der Marel, G.A., Kessler, B.M., Overkleeft, H.S., and Kisselev, A.F. (2007). A cell-permeable inhibitor and activity-based probe for the caspase-like activity of the proteasome. Bioorg Med Chem Lett 17, 3402–3405.
Verdoes, M., Berkers, C.R., Florea, B.I., van Swieten, P.F., Overkleeft, H.S., and Ovaa, H. (2006a). Chemical proteomics profiling of proteasome activity. Methods Mol Biol 328, 51–69.
Verdoes, M., Florea, B.I., Menendez-Benito, V., Maynard, C.J., Witte, M.D., van der Linden, W.A., van den Nieuwendijk, A.M., Hofmann, T., Berkers, C.R., van Leeuwen, F.W., Groothuis, T.A., Leeuwenburgh, M.A., Ovaa, H., Neefjes, J.J., Filippov, D.V., van der Marel, G.A., Dantuma, N.P., and Overkleeft, H.S. (2006b). A fluorescent broad-spectrum proteasome inhibitor for labeling proteasomes in vitro and in vivo. Chem Biol 13, 1217–1226.
Verdoes, M., Hillaert, U., Florea, B.I., Sae-Heng, M., Risseeuw, M.D., Filippov, D.V., van der Marel, G.A., and Overkleeft, H.S. (2007). Acetylene functionalized BODIPY dyes and their application in the synthesis of activity based proteasome probes. Bioorg Med Chem Lett 17, 6169–6171.
Verma, R., and Deshaies, R.J. (2000). A proteasome howdunit: the case of the missing signal. Cell 101, 341–344.
Wilk, S., and Figueiredo-Pereira, M.E. (1993). Synthetic inhibitors of the multicatalytic proteinase complex (proteasome). Enzyme Protein 47, 306–313.
Wilk, S., and Orlowski, M. (1983a). Evidence that pituitary cation-sensitive neutral endopeptidase is a multicatalytic protease complex. J Neurochem 40, 842–849.
Wilk, S., and Orlowski, M. (1983b). Inhibition of rabbit brain prolyl endopeptidase by n-benzyloxycarbonyl-prolyl-prolinal, a transition state aldehyde inhibitor. J Neurochem 41, 69–75.
Yang, H., Chen, D., Cui, Q.C., Yuan, X., and Dou, Q.P. (2006). Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 66, 4758–4765.
Yang, H., Shi, G., and Dou, Q.P. (2007). The tumor proteasome is a primary target for the natural anticancer compound Withaferin A isolated from “Indian winter cherry”. Mol Pharmacol 71, 426–437.
Yewdell, J.W. (2005). Immunoproteasomes: regulating the regulator. Proc Natl Acad Sci U S A 102, 9089–9090.
Author information
Authors and Affiliations
Editor information
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Wehenkel, M., Ho, Y., Kim, KB. (2009). Proteasome Inhibitors. In: Rubin, E., Sakamoto, K. (eds) Modulation of Protein Stability in Cancer Therapy. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69147-3_7
Download citation
DOI: https://doi.org/10.1007/978-0-387-69147-3_7
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-69143-5
Online ISBN: 978-0-387-69147-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)