Cancer treatment proteasome inhibitor

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... 

Jackson G, Einsele H, Moreau P et al (2005) Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. Cancer Treat Rev 31 591-602... 

The inhibition of multifunctional enzymes can also have therapeutic interest. The 26S proteasome is a mul-ticatalytic intracellular protease complex expressed in eukaryotic cells. This complex is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes. Thus, proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation conditions. Bortezomib and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States... 

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. 

Several human or recombinant antiproliferative proteins are currently in use for the treatment of cancer. Interleukin-2, interferons, BCG vaccine, tyrosine kinase, epidermal growth factor, proteasome inhibitors, and several monoclonal antibodies directed against tumor cell antigens now augment the cancer chemotherapeutic arsenal. (Readers are directed to Chapter 5 for a more in-depth discussion of the peptides and proteins available for the treatment of neoplastic disease.)... 

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. 

Proteasome inhibitors receive widespread attention as promising treatment options in cancer chemotherapy. One of the most promising drug candidates of this class is saUnosporamide A (53), isolated from the marine bacterium Salinispora tropica (Fig. 15.3) [54], The densely functionalized y-lactam-p-lactone pharmacophore is responsible for its irreversible binding to the p subunit of the 20S proteasome [55]. Moore et al. reported a biosynthetic synthesis of antipro-tealide (52) and were furthermore able to generate other nonnatural salinosporamide derivatives 54 with C-5 modifications... 

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