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.蛋白质N端甲基转移酶1（NTMT1）与神经发生、视网膜母细胞瘤及宫颈癌密切相关。然而，由于缺乏类药抑制剂，其药理学潜力尚未得到阐明。本研究通过对前期报道的先导化合物venglustat进行结构导向优化，发现了首个可用于体内研究的NTMT1化学探针GD433。GD433的半最大抑制浓度（IC50）为27±1.1 nM，在生化、生物物理及细胞水平的实验中，均展现出较venglustat更优的活性与选择性。GD433同时具备良好的口服生物利用度，可作为体内化学探针，用于解析Nα甲基化的药理学功能。此外，本研究还鉴定出一种与GD433结构相近的类似物YD2160，其对NTMT1无抑制活性。该活性抑制剂与阴性对照将成为研究NTMT1催化活性的生理及药理学功能的重要工具。