Structure–Activity Relationship Studies of Venglustat on NTMT1 Inhibition

The
protein N-terminal methyltransferase 1 (NTMT1) is implicated
in neurogenesis, retinoblastoma, and cervical cancer. However, its
pharmacological potentials have not been elucidated due to the lack
of drug-like inhibitors. Here, we report the discovery of the first
NTMT1 in vivo chemical probe GD433 by structure-guided
optimization of our previously reported lead compound venglustat. GD433 (IC50 = 27 ± 1.1 nM) displays improved
potency and selectivity than venglustat across biochemical, biophysical,
and cellular assays. GD433 also displays good oral bioavailability
and can serve as an in vivo chemical probe to dissect the pharmacological
roles of Nα methylation. In addition, we also identified a close
analogue (YD2160) 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.