Angew Chem Int Ed Engl. 2016 Feb 18;55(8):2911-5. doi: 10.1002/anie.201511301. Epub 2016 Jan 22.

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

Wang C¹, Abegg D¹, Hoch DG¹, Adibekian A².

Author information

1: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
2: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. alexander.adibekian@unige.ch.

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.