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Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2022 Feb 18; Vol. 27 (4). Date of Electronic Publication: 2022 Feb 18. - Publication Year :
- 2022
-
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 (IC <subscript>50</subscript> = 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 IC <subscript>50</subscript> 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.
- Subjects :
- Binding Sites
Dose-Response Relationship, Drug
Drug Design
Humans
Methylation
Models, Molecular
Molecular Conformation
Molecular Structure
Protein Binding
Structure-Activity Relationship
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Methyltransferases antagonists & inhibitors
Peptidomimetics chemistry
Peptidomimetics pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 27
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 35209173
- Full Text :
- https://doi.org/10.3390/molecules27041381