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

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

(This article belongs to the Special Issue Design and Synthesis of Chemical Probes for Epigenetic Modification Enzymes and Proteins)

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Abstract

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

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

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