Proteasome inhibitors as anticancer agents

ABSTRACT

Introduction

The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors.

Areas covered

This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The development of selective and potent proteasome inhibitors with improved pharmacological properties is described from the synthesis to their basic biological, and clinical validation.

Expert opinion

Proteasome inhibitors have transformed the treatment landscape for hematological malignancies and hold great promise for cancer therapy. Combination therapies targeting multiple pathways, the development of novel inhibitors or ‘hybrid-inhibitors,’ and the optimization of treatment protocols are key areas for future exploration. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood–brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic ‘working on’ aspect for the near future.

KEYWORDS:

• Proteasome
• inhibitors
• bortezomib
• multiple myeloma
• cancer

Article highlights

• 20S proteasome core is a hot target for hematological malignancies

• A number of small-molecule proteasome inhibitors have been identified

• Three proteasome inhibitors are clinically used and two are in phase II/III, the outcome of these trials will likely influence future drug development in the cancer treatment.

• This review covers proteasome inhibitors in the peer-reviewed literature and patents over the past 5 years

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

All authors participated in the conceptualization of the topic, literature searches, writing, and preparation of the manuscript. All the authors read and approved the final version of the manuscript.

Additional information

Funding

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) grant IG 2019 – ID.23151 to RR.