Dong, GuangpingIyamu, Iredia D.Vilseck, Jonah Z.Chen, DongxingHuang, Rong2024-06-212024-06-212022-02Dong, G., Iyamu, I. D., Vilseck, J. Z., Chen, D., & Huang, R. (2022). Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1. Molecules, 27(4), Article 4. https://doi.org/10.3390/molecules27041381https://hdl.handle.net/1805/41734Protein N-terminal methyltransferase 1 (NTMT1) recognizes a unique N-terminal X-P-K/R motif (X represents any amino acid other than D/E) and transfers 1–3 methyl groups to the N-terminal region of its substrates. Guided by the co-crystal structures of NTMT1 in complex with the previously reported peptidomimetic inhibitor DC113, we designed and synthesized a series of new peptidomimetic inhibitors. Through a focused optimization of DC113, we discovered a new cell-potent peptidomimetic inhibitor GD562 (IC50 = 0.93 ± 0.04 µM). GD562 exhibited improved inhibition of the cellular N-terminal methylation levels of both the regulator of chromosome condensation 1 and the oncoprotein SET with an IC50 value of ~50 µM in human colorectal cancer HCT116 cells. Notably, the inhibitory activity of GD562 for the SET protein increased over 6-fold compared with the previously reported cell-potent inhibitor DC541. Furthermore, GD562 also exhibited over 100-fold selectivity for NTMT1 against several other methyltransferases. Thus, this study provides a valuable probe to investigate the biological functions of NTMT1.en-USAttribution 4.0 Internationalprotein N-terminal methyltransferasepeptidomimetic inhibitorcell-permeable inhibitorstructure-based drug designArticle