title: Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA Repair Protein MGMT.
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.
authors.affiliation: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abegg
authors.affiliation: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hoch
authors.affiliation: School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva, Switzerland. alexander.adibekian@unige.ch.
authors.forename: Alexander
authors.initials: A
authors.lastname: Adibekian
mesh_terms: D004260:DNA Repair; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D040901:Proteomics
chemical_list: D004791:Enzyme Inhibitors; D019853:O(6)-Methylguanine-DNA Methyltransferase
keywords: MGMT; activity-based protein profiling; drug discovery; mass spectrometry; proteomics