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

Angewandte Chemie
Chao WangAlexander Adibekian

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 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.

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Citations

Aug 30, 2016·Current Opinion in Biotechnology·Allison M RobertsDaniel K Nomura
Feb 9, 2017·Chembiochem : a European Journal of Chemical Biology·Theodor MarsonerNathan W Luedtke
Apr 13, 2018·Chemical Communications : Chem Comm·Dominic G HochAlexander Adibekian
Jul 14, 2018·Future Medicinal Chemistry·Guohui SunYongzhen Peng
Sep 25, 2017·ChemMedChem·Daniel ProbstJean-Louis Reymond
Nov 21, 2020·Cancer Cell·David A WheelerLouis M Staudt
Mar 19, 2021·Accounts of Chemical Research·Jessica N SpradlinDaniel K Nomura
May 15, 2020·Journal of the American Chemical Society·Karine MazmanianCarmay Lim

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