Proteasome Velcade

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. 

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

Richardson PG, Hideshima T, Anderson KC (2003) Bortezomib (Velcade), a peptidyl boronic acid which is a reversible (0.6 nM Ki) proteasome inhibitor is currently in use and approved for the treatment of multiple myeloma. In addition, there are numerous ongoing clinical trials on the use of this agent for treatment of other malignant diseases Cancer Control 10 361... 

Bortezomib. Bortezomib (Velcade) inhibits pro-teasome activity in mammalian cells.11 Mammalian proteasome is responsible for degrading certain cellular proteins affecting cell function and division. By prolonging the activity of these proteins, bortezomib brings about complex changes in cell function that lead to cell dysfunction and death. Certain types of cancer, such as multiple myeloma, are more sensitive to impaired proteasome regulation, hence the use of this drug in these cancers. 

Bortezomib (Velcade) A First-in-Class Proteasome Inhibitor... 

A number of inhibitors of various tyrosine kinase enzymes are important new cancer drugs sunitinib (Sutent) is used for the treatment of certain kidney and GI cancers imatinib (Glivec) for chronic myeloid leukemia and GI tumours, and lapatinib (Tykerb/Tykerv) for breast and lung cancers. Bortezomib (Velcade), a proteasome inhibitor is used to treat multiple myeloma and is notable for being a boronic acid. 

IkB-q (inhibitor of transcription factor NF-kB)), proteins that regulate cellular adaptation to hypoxic stress (i.e., HIF-lct), and proteins related to aberrant gene expression in tumors (e.g., c-Jun, /3-catenin, IttB-a, E2F1). Proteasome inhibitors are under development as new antitumor chemotherapeutic agents and the proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the U.S. Food and Drug Administration (FDA). 

Saha MN, Jiang H, Jayakar J et al (2010) MDM2 antagonist Nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9 936-944... 

Bortezomib (velcade) (1R)-3-methyl-l-[[(2S)-1 -oxo-3-phenyl-2-[pyrazinylcarbonyl)amino] propyl]butyl]boronic acid binds to the 20S core of the 26S proteasome and reversibly inhibits its chymotrypsin-like activity. Inhibition of the proteasome disrupts multiple signaling cascades within the cell, often leading to cell death. The most important consequences of proteasome inhibition are believed to result from downregulation of NF-kB, a key transcription factor that promotes cell survival. In a similar manner, bortezomib disrupts ubiquitin-proteasome regulation of p2I, p27, and p53, which are key regulatory proteins in the cell cycle and initiators of apoptosis. 

Salinosporamide A, NPI 0052, a microbial product of Salinispora tropica strain CNB-392 that acts as a potent protea-some inhibitor. Salinosporamide A is structurally related to omuralide, the -lactone derived from lactacystin, and is more effective as a proteasome inhibitor than omuralide. Furthermore, it exhibits cytotoxicity against many tumor cell lines, especially against Velcade resistant multiple myeloma cells [V. Caubert, N. Langlois, Tetrahedron Lett. 2007, 48, 381]. 

Bortezomib (Velcade , Millenium Pharmaceuticals) is a small-molecule proteasome inhibitor used for the treatment of multiple myeloma refractory to other treatments. 

Besides their fundamental interest, proteasomes are relevant therapeutic targets. The peptide boronic acid, bortezomib (Velcade, Figure 12.2) is the first proteasome inhibitor to have reached the clinic and is used to treat late-stage multiple myeloma [4]. Originally developed as a p5-specific inhibitor, it was later on found to target also pi, pSi, and pii and, moreover, it became clear that exclusive inhibition of p5 is not sufficiently effective for tumor eradication. 

The most useful biological applications of these compounds have included the synthesis of some asymmetric insect pheromones in very high stereopurity, described in Sections 8.3.1 and 8.3.3, and the proteasome inhibitor "Velcade (bortezomib) developed by Millennium Pharmaceuticals and recently approved by the United States FDA as well as the European Union for treatment of relapsed and refractory multiple myeloma, Section 8.3.6. 

The only amido boronic acid that has reached the pharmaceutical market to date is Velcade (Millennium Pharmaceuticals, bortezomib) (125) (Figure 8.3), which received United States FDA approval, May 13, 2003, and approval by the European Union, April 27, 2004, for treatment of relapsed and refractory multiple myeloma and is undergoing clinical tests for other types of cancer [56, 57]. It is an inhibitor of proteasome 26 S, and promotes apoptosis in cancer cells that have lost the alternative proteasome. Bortezomib is the first proteasome inhibitor as well as the first boron compound to pass clinical tests and become an approved drug. 

Mimnaugh BG, Xu W, Vos M et al. (2006) Endoplasmic reticulum vacuolization and valosin-containing protein relocalization result from simultaneous hsp90 inhibition by geldanamycin and proteasome inhibition by velcade. Mol Cancer Resi(9), 667-681. 

Adams J, Kauffman M. (2004) Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22(2), 304-311. 

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