Discovery of selective fragment-sized immunoproteasome inhibitors

Kollár, Levente; Szilágyi, Bence; Proj, Matic; Knez, Damijan; Ábrányi‐Balogh, Péter; Petri, László; Imre, Tı́mea; Bajusz, Dávid; Ferenczy, György G.; Gobec, Stanislav; Keserü, György M.; Sosič, Izidor

doi:10.1016/j.ejmech.2021.113455

Cited by 12 publications

(26 citation statements)

References 76 publications

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“…HRMS measurements (ESI + , ESI -, APCI + and APCI -) were performed for all new compounds, except for 1, 2, 3, 10, and 11, which were not ionizable. This phenomenon was also observed for some other benzoxazole-2-carbonitrile derivatives [22].…”

Section: General Chemistry Methodssupporting

confidence: 71%

“…Full synthetic details (Schemes S1-S4) and spectroscopic characterization of the compounds can be found in the Supplementary Materials. First, we selected a chloro atom that could form halogen bonds in a polar environment and could also fit into apolar pockets (see Table 1 for IC 50 values) [22]. Next, hydroxyl substituents were introduced to different positions, because this substituent can participate in H-bond interactions as both a donor and an acceptor.…”

Section: Resultsmentioning

confidence: 99%

“…Hydrophobic interactions were monitored by the methyl scan (see Table 2). a IC 50 values from ref [22]; compounds showed limited stability after 1 h in the assay buffer. All benzoxazole-2-carbonitriles, 5-27, were first evaluated for their stability in the assay buffer using a UV-Vis-based high-throughput assay.…”

Section: Resultsmentioning

confidence: 99%

“…Full synthetic details ( Schemes S1–S4 ) and spectroscopic characterization of the compounds can be found in the Supplementary Materials . First, we selected a chloro atom that could form halogen bonds in a polar environment and could also fit into apolar pockets (see Table 1 for IC 50 values) [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…The selectivity of inhibitors is also crucial, as most iCP inhibitors have significant activity against multiple proteasomal subunits, leading to undesirable side-effects in clinical settings [ 5 , 20 , 21 ]. Recently, we discovered benzo[ d ]oxazole-2-carbonitriles, benzo[ d ]thiazole-2-carbonitriles, benzo[ d ]imidazole-2-carbonitriles, and 1-methylbenzo[ d ]imidazole-2-carbonitriles (using a general term: benzoXazole-2-carbonitriles) as selective fragment-sized iCP inhibitors [ 22 ]. Out of this set of benzoXazole-2-carbonitrile cores, the benzoxazole-2-carbonitrile scaffold showed the most promising inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

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Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Kollár

Gobec

Proj

et al. 2021

Cells

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Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

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Section: General Chemistry Methodssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Kollár

Gobec

Proj

et al. 2021

Cells

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Selective noncovalent proteasome inhibiting activity of trifluoromethyl‐containinggem‐quaternary aziridines

Ielo

Patamia

Citarella

et al. 2023

Archiv der Pharmazie

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The ubiquitin‐proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well‐known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis‐homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood–brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.

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Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti‐SARS‐CoV‐2 Activity

et al. 2022

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Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting the interaction between Kelch-like ECHassociated protein 1 (KEAP1) and nuclear factor erythroid 2related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger ontarget activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID-19 therapies.This article belongs to the Early-Career Special Collection, "EuroMedChem Talents".

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Discovery of selective fragment-sized immunoproteasome inhibitors

Cited by 12 publications

References 76 publications

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Selective noncovalent proteasome inhibiting activity of trifluoromethyl‐containinggem‐quaternary aziridines

Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti‐SARS‐CoV‐2 Activity

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