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Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1.

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.

SUBMITTER: Chen D 

PROVIDER: S-EPMC6760264 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1.

Chen Dongxing D   Dong Guangping G   Noinaj Nicholas N   Huang Rong R  

Journal of medicinal chemistry 20190327 7

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 (IC<sub>50</sub> = 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. ...[more]

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