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

Molecules. 2022 Feb 18;27(4):1381. doi: 10.3390/molecules27041381.

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.

Keywords: cell-permeable inhibitor; peptidomimetic inhibitor; protein N-terminal methyltransferase; structure-based drug design.

MeSH terms

  • Binding Sites
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Methylation
  • Methyltransferases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Peptidomimetics / chemistry*
  • Peptidomimetics / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Peptidomimetics
  • Methyltransferases
  • NTMT1 protein, human