Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors.

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (ß5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the ß5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure-activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.

A focused structure-activity relationship study of psoralen-based immunoproteasome inhibitors.

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the ß5i subunit of the immunoproteasome with different substituents placed at position 4'. The most promising compound was further evaluated through changes at position 3 of the psoralen ring. Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able to improve the selectivity against other subunits of both the immunoproteasome and the constitutive proteasome. The most potent compounds discriminated between both proteasome types in cell lysates and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.

A patent review of immunoproteasome inhibitors.

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.