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

Published in Angewandte Chemie: International Edition. 2016, vol. 55, no. 8, p. 2911-2915
Abstract 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 O6-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.
Keywords Activity-based protein profilingDrug discoveryMass spectrometryMGMTProteomics
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Other version: http://doi.wiley.com/10.1002/anie.201511301
Research group Groupe Adibekian
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WANG, Chao et al. Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT. In: Angewandte Chemie: International Edition, 2016, vol. 55, n° 8, p. 2911-2915. https://archive-ouverte.unige.ch/unige:81084

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Deposited on : 2016-02-29

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