Proteasome carfilzomib

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). 

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... 

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. 

In recent years, a number of structurally distinct compounds targeting the proteasome have reached the clinic, amongst others the covalent and irreversible inhibitor carfilzomib [5]. The structure of carfilzomib is based on that of the natural product, epoxomicin, that also features the epoxyketone electrophilic trap. Indeed, numerous natural product proteasome inhibitors with a distinguishing electrophile grafted onto a peptidic core have been described over the years, including lactacystin, syringolin A (SylA), and fellutamide B. An important class of synthetic covalent proteasome inhibitors is represented by the peptide vinyl sulfones, whereas numerous noncovalent proteasome inhibitors have been discovered as well (e.g., TMC 95A). 

Fig. 13.5 Proteasome inhibitors used (or intended) for the treatment of relapsed multiple myeloma, mantle cell lymphoma, and some other tumors. Structures of the peptide boronates bortezomib and the orally active MLN9708, the peptide epoxyketone carfilzomib, and the y-lactam-p-lactone bicyclics sallnosporamide A (marizomib) and omuralide (P-clastolactacystin), both derived from natural sources. The drugs inhibit normal proteasome action by binding to the p-subunit proteolytic sites in the 20S core (see Fig. 13.4)...

Newer proteasome inhibitors include the orally active peptide boronate MLN9708 and carfilzomib. Adverse reactions to carfilzomib include pulmonary hypertension, dyspnea, infusion reactions, tumor lysis syndrome, hepatotoxicity, rash, and urticaria. 

Exceptions certainly exist in the realm of clinical therapeutics such as the proteasome inhibitor carfilzomib and in the emerging chemical biology field of activity-based protein profiling (ABPP) however, without a direct hypothesis relating to electrophilic modification, early elimination of these hit compounds may prove fortuitous [25, 26]. 

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