2. Academic Validation
  3. Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies

Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies

  • J Med Chem. 2020 Sep 10;63(17):9512-9522. doi: 10.1021/acs.jmedchem.0c00689.
Brianna D Mackie 1,  Dongxing Chen 2,  Guangping Dong 2,  Cheng Dong 3,  Haley Parker 4,  Christine E Schaner Tooley 4,  Nicholas Noinaj 5,  Jinrong Min 3,  Rong Huang 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Institute of Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
  • 2 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3 Structural Genomics Consortium, Department of Physiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 4 Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, United States.
  • 5 Department of Biological Sciences, Markey Center for Structural Biology, and the Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States.
PMID: 32689795 DOI: 10.1021/acs.jmedchem.0c00689
Abstract

Protein N-terminal methyltransferases (NTMTs) methylate the α-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitor for NTMT1/2. Biochemical and cocrystallization studies manifest that BM30 (with a half-maximal inhibitory concentration of 0.89 ± 0.10 μM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. BM30 exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 MTs, indicating its potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analogue DC432 (IC50 of 54 ± 4 nM) decreases the N-terminal methylation level of the regulator of chromosome condensation 1 and SET proteins in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in the future.

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