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- W4377029351 abstract "<b>Abstract ID 23315</b> <b>Poster Board 320</b> Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. We identified venglustat as a potent inhibitor (IC<sub>50</sub> = 0.42 μM) of protein N-terminal methyltransferase 1 (NTMT1) by high throughput screening. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC<sub>50</sub> = 0.5 μM). Further structure-guided optimization of venglustat produced <b>GD433</b> (IC<sub>50</sub> = 27 ± 1.1 nM), displaying improved potency and selectivity than venglustat across biochemical, biophysical, and cellular assays. <b>GD433</b> also shows good oral bioavailability and can serve as an <i>in vivo</i> chemical probe to dissect the pharmacological roles of Na methylation. In addition, we also identified a close analogue that is inactive against NTMT1. The active inhibitor and negative control will serve as valuable tools to examine the physiological and pharmacological functions of NTMT1 catalytic activity. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide clinical investigations and enhance its selectivity to ceramide glycosyltransferase. Support/Funding Information: NIH grant U01CA214649 (RH), R01GM117275 (RH)" @default.
- W4377029351 created "2023-05-19" @default.
- W4377029351 creator A5056368645 @default.
- W4377029351 creator A5063949124 @default.
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- W4377029351 date "2023-05-18" @default.
- W4377029351 modified "2023-09-29" @default.
- W4377029351 title "Venglustat Analogues with Enhanced Inhibition for Protein N-Terminal Methyltransferases 1/2" @default.
- W4377029351 doi "https://doi.org/10.1124/jpet.122.233150" @default.
- W4377029351 hasPublicationYear "2023" @default.
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