Proteasome inhibition

Proteasomal inhibition represents a novel strategy in cancer treatment and the small molecule Bortezomid (PS-341, Velcade ) has been approved for the treatment of refractory and relapsed multiple myeloma, a proliferative disease of plasma cells. Bortezomid inhibits an active site in a proteasome subunit and remarkably shows selective cytotoxicity to cancer cells. Although the underlying mechanisms are not completely understood bortezomid apparently induces a cell stress response in these tumor cells followed by caspase-dependent apoptosis. Whether bortezomid is beneficial for the treatment of other proliferative disease is currently being tested in clinical trials. 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

Qureshi, N., Perera, P.-Y., Shen, J., Zhang, G., Lenschat, A., Splitter G., Morrison, D.C., and Vogel, S.N. (2003) The proteasome as a lipopolysaccharide-binding protein in macrophages Differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events. J. Immunol. 171, 1515. 

Compound 59 was prepared in six steps starting from iV-(/>-methoxybenzyl)glycine ethyl ester and (i )-O-acetyl-atrolactic chloride, as reported in Section 11.11.7.3. Stereoselective reduction of 59 with BH3 at the carbonyl in position 8 (the only ketone among the other carbonyls) gave compound 60 in high diastereomeric purity (>95%). This diol was further opened in basic conditions and lactonized (Scheme 5) to produce an omuralide analogue 61 which can be potentially selective for proteasome inhibition <20010L1395>. 

Vesicular trafficking and inclusion body formation are both dependent on the integrity of microtubules and other cytoskeletal components. Parkin has been shown to target misfolded tubulin for degradation [251] (figure 4.6B) and to interact with centrosomes upon proteasomal inhibition [252]. Whether this reflects association with specific substrates or co-localization with proteasomes in centrosomes re-... 

R., and Moroder, L. The core structure of TMC-95A is a promising lead for reversible proteasome inhibition. Angew. Chem. Int. 

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). 

Keck, S., Nitsch, R., Grune, T., UUiich, O. (2003) Proteasome inhibition by paired hehcal fUament-tau in brains of patients with Alzheimer s disease. J. Neurochem., 85, 115-122. 

It appears that the a-synuclein contains intramolecular cross-links possibly mediated by tissue transglutaminase (Andringa et al., 2004 Muma, 2007 Ruan and Johnson, 2007). As noted above there is a theoretical possibility that carnosine may be a competitive inhibitor for tissue transglutaminase which could prevent formation of the a-synuclein crosslinks which may prevent Lewy body formation and proteasome inhibition. 

Ding, Q. and Keller, J. N. (2001). Proteasome inhibition in oxidative stress neurotoxicity Implications for heat shock proteins. J. Neurochem. 77,1010-1017. 

Corey et al. [116] have published the synthesis of spiro-p-lactam 180 (Scheme 42), which is a synthetic intermediate for other p-lactams, which are able to inhibit proteasome. Proteasome inhibition helps in the therapy of cancer and has been evaluated for multiple myeloma [104]. 

Proteasome inhibition offers considerable promise in the therapy of a number of types of cancer and is already used for multiple myeloma [403 -05]. A potential problem with the use of compounds I or II as therapeutic agents, is their short half-life in solution at pH 7 or in serum (estimated as 5-10 min). 

Scheme 7 Saponification of bicyclic [1-lactam 21 as a test for the proteasome inhibition activity of parent compound 20...

Richardson PG, Mitsiades C, Hideshima T et al (2006) Bortezomib proteasome inhibition as an effective anticancer therapy. Annu Rev Med 57 33-47... 

P. H. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J. Biol. Chem. 2004, 279 12924-12934. 

Q. P. Dou, D.M. Smith, K.G. Daniel, and A. Kazi. Interruption of tumor cell cycle progression through proteasome inhibition implications for cancer therapy. 

The proteasome is a large multisubunit proteolytic complex that participates in the degradation of proteins critical for cell cycle regulation. The proteasome inhibitors can overcome drug resistance. This effect is thought to be mediated through prevention of activation of NF-kB (nuclear transcription factor-icB) by proteasome inhibition. NF-kB is considered as one of the key factors involved in apoptotic pathways... 

Figure 12.2 Pharmacodynamic profiles of NPI-0052 and bortezomib after a single IV administration in mice or rats. (A) Inhibition of CT-L, T-L and C-L 205 proteasome activities in packed whole blood (PWB) lysates after a single IV administration of NPI-0052 (0.15 mg/kg) or bortezomib (1 mg/kg) in mice. NPI-0052 exhibits a broader and longer 20>S proteasome inhibition profile than bortezomib.14 (B) CT-L 205 proteasome activity recovers more quickly in peripheral blood mononuclear cell (PBMQ lysates compared with PWB lysates after NPI-0052 administration to rats at 0.05 mg/kg or 0.1 mg/kg.

More importantly, proof-of-mechanism with proteasome inhibition levels in packed whole blood (inhibition of CT-L activity increasing with time and dose up to 100% Figure 12.4) reaching and exceeding those reported with therapeutic doses of bortezomib was attained at lower doses, suggesting potential for a significantly improved therapeutic ratio. Of particular interest, the profile of adverse events associated with NPI-0052 was quite different from those generally reported with bortezomib. 

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