Proteasome inhibitor

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

Yang, H. Chen, D. Cui, Q. C. Yuan, X. Dou, Q. P. Celatrol, 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. 2006, 66, 4758 -765. 

Bayot, A. Basse, N. Lee, I. Gareil, M. Pirotte, B. Bulteau, A. L. Friguet, B. Reboud-Ravaux, M. Towards the control of intracellular protein turnover mitochondrial Lon protease inhibitors versus proteasome inhibitors. Biochimie 2008, 90, 260-269. 

Bortezomib (Velcade) Proteasome inhibitor Third-line myeloma Phase II response rate... 

Meng, L. et al. Epoxomidn, a potent and selective proteasome inhibitor, exhibits in vivo anti-inflammatory activity. Proc. Natl. Acad. Sci. USA 1999, 96, 10403-10408. 

Proteasome inhibitors have been instrumental in identifying numerous protein substrates and in elucidating the importance of the proteasome/ubiquitin pathway in many biological processes. Initially, non-specific cell-penetrating peptide aldehydes were used for this purpose. More recently, it became possible to synthesize compounds with increased potency and selectivity (Adams et al. 1998 Elofsson et al. 1999). Furthermore, based on the crystal structure of the yeast and bovine liver CP (Groll et al. 1997 Unno et al. 2002), molecular modeling can now be used to engineer improved inhibitors. 

Eloesson, M., Splittgeebee, U., Myung, J., Mohan, R., and Crews, C. M. Towards subunit-specific proteasome inhibitors synthesis and evaluation of peptide alpha, beta -epoxyketones. Chem Biol 1999,... 

R., and Crews, C. M. Crystal structure of epoxomidn 20S proteasome reveals a molecular basis for selectivity of alpha, beta -epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 2000b, 122, 1237-1238. 

Koguchi, Y., Kohno, J., Nishio, M., Takahashi, K., Okuda, T., Ohnuki, T., and Komatsubaea, S. 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) 2000, 53, 105-109. 

Hat Functionality Resetting Hat Overexpression, Hat Activators, Caspase/proteasome Inhibitors... 

Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/AblJ) cells sensitive and resistant to STI571. Blood 102 3765-3774... 

Rothwell SW, Wassef NM, Alving CR, Rao M. Proteasome inhibitors block the entry of liposome-encapsulated antigens into the classical MHC class I pathway. Immunol Lett 2000 74 141. 

Belactosin A - proteasome inhibitor, antiproliferative and antitumor activities Belactosin B - inactive member... 

Figure 8 Ubiquitin and endocytosis. Receptors on the plasma membrane undergo monoubiquitination as a result of ligand (e.g., neurotransmitter). Ubiquitinated receptors bind to proteins called epsins, which in turn interact with adaptor proteins (adaptin) bound to clathrin-coated pits. Ubiquitination also functions to sort the internalized membrane protein into early endosomes, which directs them to degradation by lysosome through the multivesicular body. If ubiquitin from the endocytosed receptors is removed by an UBP, the receptor recycles back to the membrane. Proteasome inhibitors block endocytotic degradation of some proteins such as glutamate receptor subunits indicating a possible role for the proteasome.

Moreover, an UCH (Ap-uch) that interacts with the proteasome was found to be induced by 5-HT, the neurotransmitter that induced long-term facilitation. Ap-uch was found to be critical for the induction of longterm facilitation. Subsequently, Chain et al showed that at sensory-motor neuron synapses, injection of lactacystin, a specific proteasome inhibitor blocked induction of long-term facilitation. Since R subunit inhibits the activity of C subunits of PKA, the results were interpreted to suggest that the ubiquitin-proteasome pathway operates to remove inhibitory constraints on the formation of long-term memory. This has been... 

Proteasome inhibition by lactacystin and Bz-LLL-COCHO (benzol-Leu-Leu-Leu-glyoxal) causes a significant increase of ABP and cell death by altering APP processing at the y-secretase site (406). Resveratrol does not inhibit ABP production because it has no effect on 3-, or y-secretases, but promotes instead intracellular degradation of ABP via a mechanism that involves the proteasome. The resveratrol-induced decrease of ABP can be effectively prevented by several selective proteasome inhibitors and by small interfering RNA-directed silencing on the proteasome subunit P5 (407). 

Thermal and chemical cellular stresses result in the rapid disappearance of ubiquitinated histones [258,259]. The levels of ubiquitinated histones drops precipitously after human tumor cells are treated with proteasome inhibitors [260,261]. Deubiquitination of uH2A also occurs during apoptosis, with its lose coinciding with nuclear pyknosis and chromatin condensation [262,263]. 

Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, 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. 

Chauhan D, Catley L, Li G Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC. (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8 407 19. 

Tassone, P., Atadja, P., Chauhan, D., Munshi, N.C. and Anderson, KC. (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood, 108, 3441-3449. 

Gilley CB, Buller MJ, Kobayashi Y (2007) New entry to convertible isocyanides for the ugi reaction and its application to the stereocontrolled formal total synthesis of the proteasome inhibitor Omuralide. Org Lett 9 3631-3634... 

Site-directed mutagenesis and the crystal structure analysis of a proteasome-inhibitor complex identified the amino-terminal threonine (Thrl) of Thermoplasma P subunits as both, the catalytic nucleophile and the primary proton acceptor (Seemiiller et al. 1995 Lowe et al. 1995). 

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