Chen Dongxing, Dong Guangping, Deng Youchao, Noinaj Nicholas, Huang Rong
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, 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.
ACS Med Chem Lett. 2021 Mar 1;12(3):485-493. doi: 10.1021/acsmedchemlett.1c00012. eCollection 2021 Mar 11.
Protein N-terminal methyltransferases (NTMTs) catalyze the methylation of the α-N-terminal amines of proteins starting with an X-P-K/R motif. NTMT1 has been implicated in various cancers and in aging, implying its role as a potential therapeutic target. Through structural modifications of a lead NTMT1 inhibitor, , we designed and synthesized a diverse set of inhibitors to probe the NTMT1 active site. The incorporation of a naphthyl group at the N-terminal region and an -aminobenzoic amide at the C-terminal region of generates the top cell-potent inhibitor , demonstrating increased activity on both purified NTMT1 (IC of 0.34 ± 0.02 μM) and the cellular α-N-terminal methylation level of regulator of chromosome condensation 1 (RCC1, IC value of 30 μM) in human colorectal cancer HT29 cells. Furthermore, exhibits over 300-fold selectivity to several methyltransferases. This study points out the direction for the development of more cell-potent inhibitors for NTMT1.
蛋白质N端甲基转移酶（NTMTs）催化以X-P-K/R基序起始的蛋白质α-N端胺基的甲基化。NTMT1与多种癌症及衰老有关，这暗示了其作为潜在治疗靶点的作用。通过对一种先导NTMT1抑制剂进行结构修饰，我们设计并合成了一系列不同的抑制剂来探测NTMT1的活性位点。在 的N端区域引入萘基以及在C端区域引入对氨基苯甲酰胺，产生了细胞活性最强的抑制剂 ，其对纯化的NTMT1（IC为0.34±0.02μM）以及人结肠直肠癌HT29细胞中染色体凝聚调节因子1（RCC1）的细胞α-N端甲基化水平（IC值为30μM）均显示出增强的活性。此外， 对几种甲基转移酶表现出超过300倍的选择性。本研究为开发更具细胞活性的NTMT1抑制剂指明了方向。
