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. 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. 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 tripeptideepoxyketone-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.
COBISS.SI-ID: 4522609
In our research, we are focusing on the identification and development of non-peptidic compounds of both non-covalent and covalent nature that selectively inhibit the chymotrypsin-like (ß5i) subunit of the iCP. Molecules of this type have several advantages; besides better stability it is also possible to cover greater chemical and property space, providing more medicinal chemistry options during their optimization. As our initial approach to develop non-peptidic inhibitors, we used virtual-screening and subsequent chemical optimization. Biochemical evaluation of reversibly and irreversibly acting compounds showed that these non-peptidic molecules selectively block the ß5i subunit of the human iCP on cell lysates and on intact cells. Our current efforts are devoted to further improvements of the described non-peptidic inhibitors of the iCP by using scaffold morphing and scaffold hopping approaches, as well as to discovering new non-peptidic scaffolds and electrophilic warheads via screening of libraries of both non-covalent fragments and electrophilic warheads.
COBISS.SI-ID: 4469361