A patent review of immunoproteasome inhibitors

ABSTRACT

Introduction: The ubiquitin–proteasome system is responsible for maintaining protein homeostasis and regulating a variety of cellular processes. The constitutive proteasome is expressed in all cells while the immunoproteasome (IP) is predominantly found in cells of hematopoietic origin. In other cells, the expression of IP can be induced under the influence of cytokines released by T cells during acute immune and stress responses. Inhibitors of IP are of significant interest, because it is expected that selective inhibition of the IP would cause fewer adverse effects.

Areas covered: There is a considerable interest on patenting IP-specific inhibitors. Relevant patents and patent applications disclosing IP inhibitors are summarized and divided into two parts according to the chemical characteristics of compounds. We also briefly report on the biochemical methods used in the patents to profile the characteristics of IP inhibitors.

Expert opinion: Several selective inhibitors of IP with a promising ability to address autoimmune and inflammatory diseases are being developed. Peptidic compounds are prevalent and the most advanced IP-selective compounds to date, ONX-0914 and KZR-616, are tripeptide epoxyketone-based molecules. However, some patents disclose that IP-selective inhibition is possible with compounds possessing non-peptidic scaffolds indicating countless possibilities to address inhibition of IP in the future.

KEYWORDS:

• Autoimmune diseases
• immunoproteasome
• inhibitors
• ONX-0914
• peptidic and non-peptidic molecules
• proteasome

Article highlights

• Selective inhibition of the IP is expected to cause fewer adverse effects, since its expression is induced only during the course of disease processes.

• Peptidic and peptidomimetic inhibitors with an electrophilic warhead are prevalent in the patent literature but non-peptidic compounds are being developed as well.

• Irreversibly acting peptidic compounds are prone to metabolic degradation and have potential liability associated with long-term use in chronic diseases.

• Compounds with non-peptidic scaffolds indicate that there is an infinite chemical space that can be explored in the future development of IP-selective inhibitors.

• The presented series of compounds showcase the importance of achieving unique isoform- and subunit selective interactions.

Acknowledgments

The authors would like to acknowledge Frank M. Scalzo, PhD, Bard College Annandale-on-Hudson, New York, for critical reading of the manuscript.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosure

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

Additional information

Funding

This work was supported by Javna Agencija za Raziskovalno Dejavnost RS [grant number P1-0208] and Ministrstvo za Izobraževanje, Znanost in Šport [grant number C3330-17-529028 Raziskovalci-2.0-UL-FFA-529028].