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Article

Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1

1
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
2
Department of Biochemistry and Molecular Biology, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Yana Cen
Molecules 2022, 27(4), 1381; https://doi.org/10.3390/molecules27041381
Received: 21 December 2021 / Revised: 29 January 2022 / Accepted: 1 February 2022 / Published: 18 February 2022
Protein 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. View Full-Text
Keywords: protein N-terminal methyltransferase; peptidomimetic inhibitor; cell-permeable inhibitor; structure-based drug design protein N-terminal methyltransferase; peptidomimetic inhibitor; cell-permeable inhibitor; structure-based drug design
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MDPI and ACS Style

Dong, G.; Iyamu, I.D.; Vilseck, J.Z.; Chen, D.; Huang, R. Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1. Molecules 2022, 27, 1381. https://doi.org/10.3390/molecules27041381

AMA Style

Dong G, Iyamu ID, Vilseck JZ, Chen D, Huang R. Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1. Molecules. 2022; 27(4):1381. https://doi.org/10.3390/molecules27041381

Chicago/Turabian Style

Dong, Guangping, Iredia D. Iyamu, Jonah Z. Vilseck, Dongxing Chen, and Rong Huang. 2022. "Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1" Molecules 27, no. 4: 1381. https://doi.org/10.3390/molecules27041381

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