Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Biological Sciences, Markey Center for Structural Biology, and the Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States.
J Med Chem. 2023 Jan 26;66(2):1601-1615. doi: 10.1021/acs.jmedchem.2c01854. Epub 2023 Jan 12.
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 by structure-guided optimization of our previously reported lead compound venglustat. (IC = 27 ± 1.1 nM) displays improved potency and selectivity than venglustat across biochemical, biophysical, and cellular assays. 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 () 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 N-端甲基转移酶 1（NTMT1）与神经发生、视网膜母细胞瘤和宫颈癌有关。然而，由于缺乏类药抑制剂，其药理学潜力尚未得到阐明。在这里，我们通过对之前报道的先导化合物万格列斯塔（venglustat）进行结构导向优化，报告了第一个 NTMT1 的体内化学探针的发现。（IC = 27 ± 1.1 nM）在生化、生物物理和细胞测定中显示出比万格列斯塔更好的效力和选择性。（IC = 14 ± 1.1 nM）也具有良好的口服生物利用度，可以作为一种体内化学探针，用于剖析 Nα 甲基化的药理学作用。此外，我们还鉴定出一个对 NTMT1 无活性的类似物（）。活性抑制剂和阴性对照将作为研究 NTMT1 催化活性的生理和药理学功能的有价值工具。
