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

Schiffrer, Eva Shannon; Sosič, Izidor; Šterman, Andrej; Mravljak, Janez; Mlinarič-Raščan, Irena; Gobec, Stanislav

doi:10.1039/c9md00365g

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…Finally, since these compounds were previously described as inhibitors of human IP [41,42], a possible selectivity trend for either Mtb proteasome or human IP was evaluated. Both bortezomib and PR-957 appear to be selective towards the human IP, i.e., approximately 30-and 300-fold, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibitors with a peptidic backbone are prone to poor metabolic stability, and thus, exhibit low bioavailability [35,36]. Therefore, the introduction of novel, nonpeptidic IP inhibitors, such as quinolone-based compounds [37,38], oxathiazolones [39], piperlongumine analogues [40] and psoralens [41,42] has been of great importance. Nonpeptidic psoralen derivatives were identified using structure-guided virtual screening [41].…”

Section: Introductionmentioning

confidence: 99%

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Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

et al. 2020

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Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with Ki values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (Ki = 5.2 ± 1.9 µM, kinact/Ki = 96 ± 41 M−1·s−1). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

et al. 2020

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“…It penetrates cell membranes and inhibits the iCP in cells with similar selectivity as ONX 0914 but 1000-fold lower potency. To enhance target affinity, compound 3 was functionalized with different electrophilic warheads [79] and further modifications were introduced to stimulate selectivity [102]. To make use of the psoralene scaffold in future fragment evolution or linking approaches, structural analysis of the binding mode of compound 3 or one of its derivatives to the CP might be useful.…”

Section: Psoralenesmentioning

confidence: 99%

“…Although oxathiazolones are able to penetrate cell membranes, their instability in water prevented further biological studies [48]. The oxathiazolone head group has also been installed on non-covalent psoralene fragments, ultimately resulting in a potent and selective inhibitor (IC 50 for purified human CPs: 0.106 µM for β5i; residual activity of other active sites is ≥ 67% at 10 µM) [79,102]. Despite significant improvements, poor cell penetration prevented further investigations [102].…”

Section: Inhibitors Targeting Thr1mentioning

confidence: 99%

A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Huber

Groll

2021

Cells

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At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

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“…Because peptidic compounds, such as bortezomib and carfilzomib, are prone to poor metabolic stability and low bioavailability due to the unfavorable physico-chemical characteristics [ 36 , 37 , 38 ], there is a need to develop inhibitors with non-peptidic scaffolds. Despite being significantly less represented, there were some recent reports on non-peptidic inhibitors of the iCP (mostly inhibiting the β5i subunit) and the representative compounds are shown in Figure 2 [ 39 , 40 , 41 , 42 , 43 , 44 ]. As with peptidic compounds, irreversible inhibitors of non-peptidic nature can be obtained through structure-guided optimization, whereby an electrophilic warhead is properly positioned onto the structure of the non-covalently binding scaffold [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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 (β5i) 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 β5i 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.

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

Abstract: SAR exploration at a single position of the psoralen ring led to improved selectivity to the chymotrypsin-like (β5i) subunit of the immunoproteasome.

Cited by 9 publications

References 29 publications

Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

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

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