Chemoproteomics‐Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT

Chao, Wang; Abegg, Daniel; Hoch, Dominic Gregor; Adibekian, Alexander

doi:10.1002/anie.201511301

Cited by 45 publications

(38 citation statements)

References 36 publications

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“…After each MGMT molecule transfers the methyl group from O 6 ‐meG, it will deactivate itself. Therefore, the cytotoxicity of TMZ is theoretically determined by the expression level of MGMT . Because of these factors, much effort has been directed towards increasing the TMZ chemosensitivity by downregulating the expression of MGMT of glioma cells.…”

Section: Discussionmentioning

confidence: 99%

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, many GBM patients are resistant to TMZ. Therefore, patients with GBM urgently need more effective therapeutic options. 20(S)‐ginsenoside‐Rg3 (20(S)‐Rg3) is a natural chemical with anti‐tumor effects, but at present there is little understanding of its functional mechanism. Several research reports have demonstrated that O6‐methylguanine DNA‐methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ resistance in gliomas. In addition, recent studies have shown that MGMT gene expression could be regulated by the Wnt/β‐catenin pathway. However, whether 20(S)‐Rg3 inhibits MGMT expression and augments chemosensitivity to Temozolomide (TMZ) in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)‐Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM‐XX; all of them are MGMT‐positive glioma cell lines) and xenograft glioma models to examine whether 20(S)‐Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)‐Rg3 via the Wnt/β‐catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)‐Rg3. Meanwhile, 20(S)‐Rg3 shows no obvious cytotoxicity at its effective dose and is well tolerated in vivo. In addition, we found that 20(S)‐Rg3 significantly restrains the epithelial‐mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)‐Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ‐resistant GBM with high MGMT expression.

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Section: Discussionmentioning

confidence: 99%

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

et al. 2018

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“…215 Wang has recently published the use of chloromethyl triazoles (CMTs) as a new warhead for covalent inhibitor. 226 A range of CMTs were synthesized using RuAAC and their activity against O 6 -alkylguanine DNA methyltransferase (MGMT) was determined, with 139 ( Fig. 24) being identified as a potent and selective covalent inhibitor of MGMT.…”

Section: Target-oriented Medicinal Chemistrymentioning

confidence: 99%

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

et al. 2016

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The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry and the construction of 2 electronic devices. This review discusses the mechanism, scope and applications of the RuAAC reaction, covering the literature during the last 10 years. CONTENTS

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“…In another example, Wang et al showed that chloromethyltriazoles were a promising cysteine-reactive scaffold and that its reactivity could be tempered to confer selectivity for certain cysteines over others. The authors showcase a cloromethyltriazole AA-CW236 as the first potent, selective, non-pseudosubstrate inhibitor of the O(6)-alkyguanine DNA methyltransferase (MGMT) [46]. …”

Section: Abpp With Reactivity-based Probes or Reactive Chemical Smentioning

confidence: 99%

Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots

Roberts

Ward

Nomura

2017

Current Opinion in Biotechnology

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Despite the completion of human genome sequencing efforts nearly 15 years ago that brought with it the promise of genome-based discoveries that would cure human diseases, most protein targets that control human diseases have remained largely untranslated, in-part because they represent difficult protein targets to drug. In addition, many of these protein targets lack screening assays or accessible binding pockets, making the development of small-molecule modulators very challenging. Here, we discuss modern methods for activity-based protein profiling-based chemoproteomic strategies to map “ligandable” hotspots in proteomes using activity and reactivity-based chemical probes to allow for pharmacological interrogation of these previously difficult targets. We will showcase several recent examples of how these technologies have been used to develop highly selective small-molecule inhibitors against disease-related protein targets.

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Chemoproteomics‐Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT

Cited by 45 publications

References 36 publications

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

20(S)‐ginsenoside‐Rg3 reverses temozolomide resistance and restrains epithelial‐mesenchymal transition progression in glioblastoma

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots

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