Proteasome bortezomib

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. 

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. 

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

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... 

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. 

Adams J, Elliott PJ, Bouchard P (2004) Preclinical development of bortezomib (Vel-cade) Rationale for clinical studies. In Adams J (ed) Proteasome inhibitors in cancer therapy. Humana Press, Totowa, NJ, p 233... 

Bortezomib is the hrst therapeutic proteasome inhibitor. It inhibits the activity of the 26S-proteasoom protein complex which regulates protein expression and function and thus plays a role for cell homeostasis. It is used for the treatment of relapsed mulh-ple myeloma. Following intravenous administrahon bortezomib is mainly metabolised with an elimina-hon halflife of 5-15 h. It is frequently associated with somehmes irreversable neuropathy. Myelosuppression may be dose limiting. 

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. 

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... 

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

Chauhan D, Catley L, Li G et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8 407 119... 

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

These mechanistic findings supported the exploration of the therapeutic potential of proteasome inhibitors in oncology, with the first clinical trials involving a proteasome inhibitor (bortezomib) commencing about ten years ago. Lessons learned from bench to bedside during this time period have recently been reviewed.19... 

Elucidation of the role of the 205 proteasome in protein degradation and as a target for cancer chemotherapy could not have been achieved without small molecule inhibitors, some of which have served strictly as research tools, while others have progressed through preclinical development and clinical trials.18,28,29 These molecules represent a variety of structural classes, including peptide boronic acids such as bortezomib and CEP-187 70,30 epoxyketones (e.g. carfilzomib)31 and the y-lactam-(3-lactone family of inhibitors (Figure 12.1). 

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.

Our initial findings that NPI-0052 inhibited all three proteolytic functions of the IDS proteasome vide supra) led us to compare its profile with other proteasome inhibitors (Figure 12.1) such as bortezomib,14 carfilzomib (PR-171)31 and CEP-187 70.30 These agents inhibit the CT-L activity to a similar degree as NPI-0052 but exhibit different inhibition profiles for the T-L and C-L activities. In addition, NPI-0052 exhibits a different recovery profile of proteasome functions in whole blood, normal organs, tumour and peripheral blood mononuclear cell preparations compared with other agents.52... 

Our studies clearly differentiate NPI-0052 from other proteasome inhibitors in the speed and duration of action and the inhibition profile of the 20S proteasome. These differences and the possible off-target activities of bortezomib indicate that NPI-0052 may provide a greater therapeutic index and greater activity in diseases where bortezomib shows minimal activity.64... 

The pharmacodynamic profile of NPI-0052 is different from other proteasome inhibitors (bortezomib and carfilzomib) in that upon a single IV administration to mice, a sustained inhibition ( > 72 hours) of the main three 20.S proteolytic activities is observed in packed whole blood lysates (Figure 12.2A). Bortezomib has been reported to either have no effect on or to enhance the T-L activity, while carfilzomib specifically inhibits the CT-L 20V proteasome activity.14,31 Repeated NPI-0052 administration to rodents and monkeys leads to sustained dose-dependent inhibition of whole blood 20V proteasome activity, with higher inhibition observed after subsequent administrations and with partial recovery between consecutive NPI-0052 treatments. 

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. 

---