Proteasome Inhibitors in Preclinical Evaluation
Preclinical evaluations are ongoing for a number of compounds that demonstrate the ability to inhibit the proteasome. Among these is lactacystin, a natural product isolated from Streptomyces and a member of the family of γ-lactam-β-lactones. Lactacystin is a prodrug whose active form, omuralide, is generated spontaneously in vivo. There is considerable interest in omuralide because of its potent and selective inactivation of the 20S proteasome. Epoxomicin and eponemycin are natural epoxyketone products shown to be specific, potent, irreversible PIs with unique mechanisms of action on the proteasome. TMC-95A is a natural product of Apiospora montagnei that inhibits the CT-L, C-L, and T-L activities of the proteasome. Due to its unique structure and mechanism of inhibition, there have been attempts to manufacture TMC-95A, even though its activity has yet to be thoroughly evaluated. Another natural product, fellutamide B, has been isolated from Penicllium fellutanum. It is a peptide-aldehyde that strongly inhibits CT-L activity and, to a lesser extent, T-L activity of the proteasome. These results suggest that further investigation is warranted and that the number of clinically active PIs is likely to expand.
Rationale for Targeting the Immunoproteasome
The constitutive proteasome is found in most cell types. Most of the clinically effective PIs exert their primary effect on the constitutive proteasome, which can result in toxicities that limit the dose that can be used in patients, consequently reducing therapeutic efficacy. The immunoproteasome is expressed predominantly in immune cells and at much lower levels in other cells, although induction is possible following exposure to cytokines released in response to viral infections or induced by immune stress. Kuhn et al tested a variety of immunoproteasome-specific inhibitors (IPSIs) in lymphoid-derived cell lines and patient-derived samples and found that one compound, IPSI-001, preferentially inhibited the proteasome and induced apoptosis in cells of lymphoid origin. These results suggest that while IPSIs may have cytotoxic properties similar to those of PIs, they may be less toxic to nonhematopoietic cells. IPSI-001 demonstrated synergistic activity with dexamethasone(Drug information on dexamethasone) and was also found to overcome resistance to bortezomib(Drug information on bortezomib). ONX 0914 (formerly PR-957) and the related compound PR-924 are selective inhibitors of the immunoproteasome subunit LMP7. PR-924 significantly inhibited growth of MM cell lines in a time-dependent and dose-dependent manner, without pronounced effects on normal peripheral blood mononuclear cells. Together, these findings highlight the potential of the immunoproteasome as a relevant therapeutic target in MM.
IPSIs have the potential to offer enhanced efficacy in MM while simultaneously limiting adverse effects. However, the relationship between inhibition of specific active sites on the immunoproteasome and the actual therapeutic activity of these new inhibitors has yet to be evaluated in clinical trials.
The Place of Next-Generation PIs in MM Therapy
It is likely that next-generation agents will become increasingly important as their differentiating features become better defined; these include their ability to overcome drug resistance, their reduced toxicity, and the ability to administer them in more convenient dosing schedules. It also may be possible to employ PIs as combination therapy with otherwise suboptimal doses of conventional chemotherapeutics. These combinations could improve the efficacy of standard regimens and improve tolerability, while at the same time reducing the potential for the emergence of drug resistance. Also, there is the possibility that combining PIs with distinct proteasomal-binding profiles may result in synergistic inhibitory effects on the proteasome, leading to enhanced activity.
The development of next-generation PIs represents a major therapeutic advance in MM and may further strengthen the role of PIs as the foundation of anti-MM therapy. These second-generation agents may help to overcome some of the limitations of current therapies. Encouraging results from preclinical and early clinical studies suggest that these agents are more selective and cause less toxicity than bortezomib. Future challenges include the development of inhibitors with enhanced pharmacologic profiles, including more selective proteasome-binding kinetics, improved tissue distribution, high oral bioavailability, and reduced need for frequent dosing. Ultimately, only clinical studies will determine whether these enhancements will translate into improved efficacy and safety of the next-generation PIs.
Acknowledgments: The authors thank CatherineSimonson, PhD, and Brian Szente, PhD, of Fishawack Communications for assistance with manuscript development. Editorial support was funded by Onyx Pharmaceuticals.