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Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy

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Inhibition of the proteasome (a highly abundant enzymatic complex responsible for intracellular protein turnover) is an effective anti-cancer therapeutic approach, as demonstrated by the first-in-class agent bortezomib. Various new proteasome inhibitors are now in development, including peptide boronic acid analogs MLN9708 and CEP-18770, peptide epoxyketones carfilzomib and PR-047, and NPI-0052, a β-lactone compound. All are potent inhibitors of proteasome activity in vitro but show differences in enzyme binding kinetics, which might affect their pharmacology and result in different efficacy and safety profiles. Here, we review the second-generation proteasome inhibitors and assess the potential pharmacologic impact of their different chemical properties.

Introduction

Inhibition of the proteasome has emerged as a clinically effective anti-cancer therapeutic approach over the past decade [1]. This has been primarily for hematologic malignancies – including multiple myeloma (MM) [2], non-Hodgkin's lymphoma (NHL) [3], and Waldenström's macroglobulinemia (WM) – and associated conditions, such as primary systemic amyloidosis. The first-in-class proteasome inhibitor bortezomib (VELCADE®, Millennium Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) has demonstrated the feasibility of this approach and validated the concept of proteasome inhibition [1]. Preclinical studies have suggested that proteasome inhibition with bortezomib results in pleiotropic effects, disrupting multiple cellular signaling pathways and inducing tumor cell death 1, 4. Clinical studies have established substantial activity of bortezomib in various malignancies, as reviewed elsewhere 2, 3, and also determined its pharmacokinetics and pharmacodynamics and characterized its safety profile [5].

Some limitations of bortezomib exist, including limited activity in solid tumors [1], emergence of reversible peripheral neuropathy in several patients [6] and the intravenous route of administration. Thus, several new proteasome inhibitors are in development, with the aim of building on the activity seen with bortezomib while improving the safety profile of proteasome inhibition and the convenience of administration. Here, we discuss the key aspects of the development of new proteasome inhibitors, review this second generation of agents and assess the potential pharmacologic impact of the different chemical properties of these agents.

Section snippets

The proteasome as a therapeutic target

The proteasome is a crucial component of the ubiquitin–proteasome system (UPS) 7, 8, 9, which is responsible for regulation and degradation of the majority of intracellular proteins. Consequently, its inhibition affects numerous signaling pathways in cells. UPS substrates include proteins responsible for regulating cellular processes such as the cell cycle, growth and proliferation signaling, and pro-apoptotic and anti-apoptotic signaling.

The 26S proteasome comprises a 20S core (Figure 1)

Mechanism of action of proteasome inhibition

Several putative mechanisms of activity of proteasome inhibition have been determined based upon preclinical studies of bortezomib. Bortezomib induces apoptosis in tumor cells via the intrinsic mitochondrial pathway, the extrinsic death-receptor pathway, and the endoplasmic reticulum stress response pathway 4, 26, 27. This activity has been suggested to result from inhibition of the degradation of various regulatory and pro-apoptotic proteins [4], including: inhibition of nuclear factor (NF)-κB

Preclinical studies and clinical development of the second-generation inhibitors

Bortezomib resulted in substantial anti-tumor activity in in vitro and in vivo studies and, through the multiple pathways affected by proteasome inhibition, demonstrated synergistic activity with various conventional and novel therapeutic agents [10]. Similar findings have been reported from preclinical studies of the second-generation inhibitors, as discussed below, although some preclinical studies have suggested differential effects and differential anti-tumor activity between proteasome

Pharmacologic implications of proteasome abundance and different binding kinetics

The challenge of developing new proteasome inhibitors is not to make them better inhibitors of the proteasome per se; as discussed earlier, bortezomib and the second-generation inhibitors all have low nanomolar IC50 values for the β5 subunit and, therefore, are very effective inhibitors of proteasome activity. Indeed, the small differences in potency between inhibitors seen in vitro might have no effect in vivo owing to the abundance of proteasomes in the human body, as illustrated in Figure 3;

Concluding remarks

The concept of proteasome inhibition as a therapeutic approach in cancer is now well established, and numerous companies are now developing new proteasome inhibitors with the aim of building upon the success of the first-in-class inhibitor bortezomib [62]. Bortezomib and all these second-generation compounds represent highly effective inhibitors of the proteasome, regardless of the type of agent; improving upon bortezomib, therefore, will require modification of the pharmacology of the

Acknowledgments

The authors acknowledge editorial assistance from Steve Hill of FireKite during the development of this publication, which was funded by Millennium Pharmaceuticals, Inc.

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