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Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1
Dongxing Chen1, Guangping Dong1, Nicholas Noinaj2
1Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery , Purdue University , West Lafayette , Indiana 47907 , United States.
Abstract:
Protein N-terminal methyltransferase 1 (NTMT1) plays an important role in regulating mitosis and DNA repair. Here, we describe the discovery of a potent NTMT1 bisubstrate inhibitor 4 (IC50 = 35 ± 2 nM) that exhibits greater than 100-fold selectivity against a panel of methyltransferases. We also report the first crystal structure of NTMT1 in complex with an inhibitor, which revealed that 4 occupies substrate and cofactor binding sites of NTMT1.
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