Ubiquitin-based anticancer therapy: Carpet bombing with proteasome inhibitors vs surgical strikes with E1, E2, E3, or DUB inhibitors

Abstract

The proteasome inhibitor bortezomib remains the only ubiquitin pathway effector to become a drug (VELCADE®) and has become a successful treatment for hematological malignancies. While producing a global cellular effect, proteasome inhibitors have not triggered the catastrophe articulated initially in terms such as "buildup of cellular garbage". Proteasome inhibitors, in fact, do have a therapeutic window, although in the case of the prototype bortezomib it is small owing to peripheral neuropathy, myelosuppression and, as recently reported, cardiotoxicity [1]. Currently, several second-generation molecules are undergoing clinical evaluation to increase this window. An alternative strategy is to target ubiquitin pathway enzymes acting at non-proteasomal sites-E1, E2, and E3, associated with ubiquitin conjugation, and deubiquitylating enzymes ("DUBs")-that act locally on selected targets rather than on the whole cell. Inhibitors (or activators, in some cases) of these enzymes should be developable as selective antitumor agents with toxicity profiles superior to that of bortezomib. Various therapeutic hypotheses follow from known cellular mechanisms of these target enzymes; most hypotheses relate to cancer, reminiscent of the FDA-approved protein kinase inhibitors now marketed. Since ubiquitin tagging controls the cellular content, activity, or compartmentation of proteins associated with disease, inhibitors or activators of ubiquitin conjugation or deconjugation are predicted to have an impact on disease. For practical and empirical reasons, inhibitors of ubiquitin pathway enzymes have been the favored therapeutic avenue. In approximately the time that has elapsed since the approval of bortezomib in 2003, there has been some progress in developing potential anticancer drugs that target various ubiquitin pathway enzymes. An E1 inhibitor and inhibitors of E3 are now in clinical trial, with some objective responses reported. Appropriate assays and/or rational design may uncover improved inhibitors of these enzymes, as well as E2 and DUBs, for further development. Presently, it should become clear whether one or both of the two general strategies for ubiquitin-based drug discovery will lead to truly superior new medicines for cancer and other diseases. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics.

Curcusone D, a novel ubiquitin–proteasome pathway inhibitor via ROS-induced DUB inhibition, is synergistic with bortezomib against multiple myeloma cell growth

“…Until recently, there have been no UPP component regulators approved by the FDA except proteasomal inhibitors. An E1 inhibitor and inhibitors of E3 are now in clinical trials, whereas no E2 or DUB inhibitors have entered clinical trials [19,27]. In recent years, some small-molecule DUB inhibitors have been identified possessing good selectivity against 19S RPassociated DUBs (USP14 and UCH-L5) such as b-AP15 [24], but most of the DUB inhibitors have poor selectivity.…”

“…Curcusone D shares no structural or chemical resemblance to any known DUB inhibitors [19][20][21][22][23][24] despite its ability to inhibit the activities of many cellular DUBs (Fig. 4C), establishing it as a new, partially selective DUB inhibitor.…”

Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit

“…Proteasome inhibitors have been widely used to characterize the UPS function and enabled dissection of important cellular pathways involved in the degradation of misfolded proteins, cell cycle, inflammatory and ARTICLE immune response, disease development, metabolism, circadian rhythms, photomorphogenesis and muscle atrophy 6 . The activity of proteasome inhibitors as anti-cancer, anti-inflammatory, angiostatic and immunomodulating agents was reported 6 , and their clinical potential as cancer chemotherapeutics has been amply documented 7,52,53 . Particularly, bortezomib (Velcade) was the first proteasome inhibitor to be tested in humans and is approved for the treatment of multiple myeloma and mantle cell lymphoma 54 .…”

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

“…Inhibition of NEDD8-associated E1 enzyme by MLN4924, E2 enzyme hCdc34 by CC0651, and E3 ligase MDM2 by RITA (NSC652287) and MI-219 reflects this ongoing effort (3). Deubiquitinases (DUB) are another class of emerging anticancer target that regulate specific substrate proteins by reversing their ubiquitination through the hydrolysis of isopeptide or a-peptide bonds linking ubiquitin to the target protein (4).…”