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Chemoproteomics‐Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT
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Chao Wang Daniel Abegg Dominic G. Hoch Prof. Dr. Alexander Adibekian 《Angewandte Chemie (International ed. in English)》2016,55(8):2911-2915
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. 相似文献
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Abegg R Baldisseri A Boudard A Briscoe W Fabbro B Garçon M Hermes EA Jacobs WW Kessler RS Lytkin L Mayer B Nefkens BM Niebuhr C Petrov AM Poitou J Saudinos J Tippens B Tomasi-Gustafsson E van der Schaaf A van Oers WT Vigdor SE Wang M White D 《Physical review D: Particles and fields》1994,50(1):92-103
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Raoult Beckmann Loomis Nernst Abegg Hamburger Eykman Ramsay Berthelot Pettersson Batelli Bruner und Arrhenius 《Fresenius' Journal of Analytical Chemistry》1903,42(1):41-47
Ohne Zusammenfassung 相似文献
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Angular distributions of cross sections [α(θ)] and vector analyzing powers [iT11(γ)] have been measured for seven low-lying states or groups of states excited by the 48Ca(, t)47Ca reaction with 13.5 MeV deuterons and analyzed by the DWBA. On the basis of comparison of vector analyzing powers with DWBA calculations, spin-parity assignments have been made or confirmed for several states. Spectroscopic factors have been extracted. Angular distributions for weak states at 3.30 and 3.57 MeV excitation in 47Ca could not be reproduced by DWBA calculations. Investigations of compound nucleus and multi-step contributions to the cross sections and analyzing powers for these states have been made by means of Hauser-Feshbach and CCBA calculations. Optical model parameters were obtained from analysis of 13.5 MeV deuteron elastic scattering cross sections and analyzing powers. 相似文献