Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT
| Autor: | Daniel Abegg, Chao Wang, Alexander Adibekian, Dominic Gregor Hoch |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Proteomics
0301 basic medicine DNA Repair DNA repair 010402 general chemistry 01 natural sciences DNA methyltransferase Catalysis O(6)-Methylguanine-DNA Methyltransferase 03 medical and health sciences Drug Discovery DNA Repair Protein medicine Chemoproteomics Enzyme Inhibitors Temozolomide Mass spectrometry Drug discovery Chemistry Activity-based proteomics O-6-methylguanine-DNA methyltransferase General Chemistry Molecular biology 0104 chemical sciences 030104 developmental biology ddc:540 Activity-based protein profiling Cancer research MGMT medicine.drug |
| Zdroj: | Angewandte Chemie: International Edition, Vol. 55, No 8 (2016) pp. 2911-2915 |
| ISSN: | 1433-7851 |
| DOI: | 10.1002/anie.201511301 |
| Popis: | We present a novel chemical scaffold for cysteine-reactive covalent inhibitors. Chloromethyl triazoles (CMTs) are readily accessed in only two chemical steps, thus enabling the rapid optimization of the pharmacological properties of these inhibitors. We demonstrate the tunability of the CMTs towards a specific biological target by synthesizing AA-CW236 as the first potent non-pseudosubstrate inhibitor of the O(6) -alkylguanine DNA methyltransferase (MGMT), a protein of major clinical significance for the treatment of several severe cancer forms. Using quantitative proteomics profiling techniques, we show that AA-CW236 exhibits a high degree of selectivity towards MGMT. Finally, we validate the effectiveness of our MGMT inhibitor in combination with the DNA alkylating drug temozolomide in breast and colon cancer cells by fluorescence imaging and a cell-viability assay. Our results may open a new avenue towards the development of a clinically approved MGMT inhibitor. |
| Databáze: | OpenAIRE |
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