Comparative reactivity analysis of small-molecule thiol surrogates

Petri, László; Ábrányi‐Balogh, Péter; Varga, Petra Regina; Imre, Tı́mea; Keserü, György M.

doi:10.1016/j.bmc.2020.115357

Cited by 30 publications

(26 citation statements)

References 43 publications

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“…Testing the compounds against N -acetyl cysteine (see protocol in the Materials and Methods section and in Figure S1 ) showed that they were hyperreactive, which prevented the determination of half-lives ( Table S1 ). The reactivity of seven compounds ( 5 – 7 , 9 , 22 , 25 , and 26 ) was also tested against glutathione (GSH) (see protocol in the Materials and Methods section), since in an earlier study GSH had a different reactivity profile compared with N -acetyl cysteine [ 24 ]. The methoxy-substituted compounds ( 6 , 7 , and 9 ) were also hyperreactive in this assay.…”

Section: Resultsmentioning

confidence: 99%

“…GSH reactivity assay was performed as described by Petri et al [ 24 ]; 500 μM solution of compound (PBS buffer pH 7.4, 10% MeCN, 250 μL) with 200 μM solution of indoprofen as internal standard were added to 10 mM GSH solution (dissolved in PBS buffer, 250 μL) in a 1:1 ratio. The final concentration was 250 μM compound, 100 μM indoprofen, 5 mM GSH and 5% MeCN (500 μL).…”

Section: Methodsmentioning

confidence: 99%

“…The final concentration was 250 μM compound, 100 μM indoprofen, 5 mM GSH and 5% MeCN (500 μL). The final mixture was analyzed by HPLC after 0, 1, 2, 4, 8, 12, 24, 48, and 72 h. The degradation kinetics were also studied using the method described in [ 24 ], except that pure PBS buffer was used instead of GSH solution. In this experiment, the final concentration of the mixture was 250 μM fragment, 100 μM indoprofen and 5% MeCN.…”

Section: Methodsmentioning

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: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

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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“…Generally speaking, the reactivity of covalent inhibitors with the targeted cysteine is crucial for covalent drug development, considering that the hyper-reactivity of the warheads may trigger potential side effects, e.g., drug-induced toxicity or immunogenicity [ 43 , 44 ]. Consequently, the reactivity of three hit compounds was measured by a GSH assay which is usually used to estimate the reactivity of cysteine-targeted warheads [ 45 ]. The resulting half-lives ( t 1/2 ) of compounds 3 and 8 were 103 and 90 min, respectively, while that of compound 2 was less than 2.5 min ( Fig.…”

Section: Resultsmentioning

confidence: 99%

In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease

Xiong

Nie

Shao

et al. 2022

European Journal of Medicinal Chemistry

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease (3CL pro ) has been regarded as an extremely promising antiviral target for the treatment of coronavirus disease 2019 (COVID-19). Here, we carried out a virtual screening based on commercial compounds database to find novel covalent non-peptidomimetic inhibitors of this protease. It allowed us to identify 3 hit compounds with potential covalent binding modes, which were evaluated through an enzymatic activity assay of the SARS-CoV-2 3CL pro . Moreover, an X-ray crystal structure of the SARS-CoV-2 3CL pro in complex with compound 8 , the most potent hit with an IC 50 value of 8.50 μM, confirmed the covalent binding of the predicted warhead to the catalytic residue C145, as well as portrayed the interactions of the compound with S1’ and S2 subsites at the ligand binding pocket. Overall, the present work not merely provided an experiment-validated covalent hit targeting the SARS-CoV-2 3CL pro , but also displayed a prime example to seeking new covalent small molecules by a feasible and effective computational approach.

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“…It is known that acetylenes do react with thiols. This may happen by means of a radical reaction (“thiol-yne-reaction” requiring a radical initiator [ 85 , 86 ]) but is also possible by means of a nucleophilic addition [ 87 ]. Thus, it cannot be excluded that the observed covalently modified C/EBPβ LAP* peptide fragments were actually formed by reaction with the acetylene group of HM.…”

Section: Sesquiterpene Lactonesmentioning

confidence: 99%

Natural Products with Antitumor Potential Targeting the MYB-C/EBPβ-p300 Transcription Module

Schmidt

Klempnauer

2022

Molecules

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The transcription factor MYB is expressed predominantly in hematopoietic progenitor cells, where it plays an essential role in the development of most lineages of the hematopoietic system. In the myeloid lineage, MYB is known to cooperate with members of the CCAAT box/enhancer binding protein (C/EBP) family of transcription factors. MYB and C/EBPs interact with the co-activator p300 or its paralog CREB-binding protein (CBP), to form a transcriptional module involved in myeloid-specific gene expression. Recent work has demonstrated that MYB is involved in the development of human leukemia, especially in acute T-cell leukemia (T-ALL) and acute myeloid leukemia (AML). Chemical entities that inhibit the transcriptional activity of the MYB-C/EBPβ-p300 transcription module may therefore be of use as potential anti-tumour drugs. In searching for small molecule inhibitors, studies from our group over the last 10 years have identified natural products belonging to different structural classes, including various sesquiterpene lactones, a steroid lactone, quinone methide triterpenes and naphthoquinones that interfere with the activity of this transcriptional module in different ways. This review gives a comprehensive overview on the various classes of inhibitors and the inhibitory mechanisms by which they affect the MYB-C/EBPβ-p300 transcriptional module as a potential anti-tumor target. We also focus on the current knowledge on structure-activity relationships underlying these biological effects and on the potential of these compounds for further development.

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Comparative reactivity analysis of small-molecule thiol surrogates

Cited by 30 publications

References 43 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

In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease

Natural Products with Antitumor Potential Targeting the MYB-C/EBPβ-p300 Transcription Module

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