Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

Chen, Dongxing; Dong, Guangping; Noinaj, Nicholas; Huang, Rong

doi:10.1021/acs.jmedchem.9b00206

Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

Journal Article · Thu Feb 28 00:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.9b00206· OSTI ID:1604173

Chen, Dongxing ^[1]; Dong, Guangping ^[1]; Noinaj, Nicholas ^[1]; ^[1]

Purdue Univ., West Lafayette, IN (United States)

Protein N-terminal methyltransferase 1 (NTMT1) plays an important role in regulating mitosis and DNA repair. Here, we describe the discovery of a potent NTMT1 bisubstrate inhibitor 4 (IC₅₀ = 35 ± 2 nM) that exhibits greater than 100-fold selectivity against a panel of methyltransferases. We also report the first crystal structure of NTMT1 in complex with an inhibitor, which revealed that 4 occupies substrate and cofactor binding sites of NTMT1.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

OSTI ID:: 1604173

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 7 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (30)

Chemical Biology of Protein N‐Terminal Methyltransferases Huang, Rong ChemBioChem, Vol. 20, Issue 8 https://doi.org/10.1002/cbic.201800615	journal	February 2019
The occurrence of α-N-trimethylalanine as the N -terminal amino acid of some myosin light chains Henry, Gillian D.; Dalgarno, David C.; Marcus, G. FEBS Letters, Vol. 144, Issue 1 https://doi.org/10.1016/0014-5793(82)80558-9	journal	July 1982
2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines Fukuyama, Tohru; Jow, Chung-Kuang; Cheung, Mui Tetrahedron Letters, Vol. 36, Issue 36 https://doi.org/10.1016/0040-4039(95)01316-A	journal	September 1995
Occurrence of methylated amino acids as N-termini of proteins from Escherichia coli ribosomes Chen, Robert; Brosius, Jürgen; Wittmann-Liebold, Brigitte Journal of Molecular Biology, Vol. 111, Issue 2 https://doi.org/10.1016/S0022-2836(77)80121-6	journal	April 1977
New strategy for the synthesis of 3-substituted prolines Karoyan, Philippe; Chassaing, Gérard Tetrahedron Letters, Vol. 38, Issue 1 https://doi.org/10.1016/S0040-4039(96)02221-6	journal	January 1997
A coupled fluorescent assay for histone methyltransferases Collazo, Evys; Couture, Jean-François; Bulfer, Stacie Analytical Biochemistry, Vol. 342, Issue 1 https://doi.org/10.1016/j.ab.2005.04.007	journal	July 2005
A direct, ratiometric, and quantitative MALDI–MS assay for protein methyltransferases and acetyltransferases Richardson, Stacie L.; Hanjra, Pahul; Zhang, Gang Analytical Biochemistry, Vol. 478 https://doi.org/10.1016/j.ab.2015.03.007	journal	June 2015
Development of novel bisubstrate-type inhibitors of histone methyltransferase SET7/9 Mori, Shuichi; Iwase, Kenta; Iwanami, Naoko Bioorganic & Medicinal Chemistry, Vol. 18, Issue 23 https://doi.org/10.1016/j.bmc.2010.10.022	journal	December 2010
NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging Bonsignore, Lindsay A.; Tooley, John G.; Van Hoose, Patrick M. Mechanisms of Ageing and Development, Vol. 146-148 https://doi.org/10.1016/j.mad.2015.03.012	journal	March 2015
Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara Neuron, Vol. 85, Issue 1 https://doi.org/10.1016/j.neuron.2014.12.031	journal	January 2015
Discovery of Bisubstrate Inhibitors of Nicotinamide N -Methyltransferase (NNMT) Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling Journal of Medicinal Chemistry, Vol. 61, Issue 4 https://doi.org/10.1021/acs.jmedchem.7b01422	journal	January 2018
Identification and Functional Characterizations of N-Terminal α- N -Methylation and Phosphorylation of Serine 461 in Human Poly(ADP-ribose) Polymerase 3 Dai, Xiaoxia; Rulten, Stuart L.; You, Changjun Journal of Proteome Research, Vol. 14, Issue 6 https://doi.org/10.1021/acs.jproteome.5b00126	journal	April 2015
Identification of Protein N-Terminal Methyltransferases in Yeast and Humans Webb, Kristofor J.; Lipson, Rebecca S.; Al-Hadid, Qais Biochemistry, Vol. 49, Issue 25 https://doi.org/10.1021/bi100428x	journal	June 2010
Identification of Novel α-N-Methylation of CENP-B That Regulates Its Binding to the Centromeric DNA Dai, Xiaoxia; Otake, Koichiro; You, Changjun Journal of Proteome Research, Vol. 12, Issue 9 https://doi.org/10.1021/pr400498y	journal	August 2013
NRMT is an α-N-methyltransferase that methylates RCC1 and retinoblastoma protein Schaner Tooley, Christine E.; Petkowski, Janusz J.; Muratore-Schroeder, Tara L. Nature, Vol. 466, Issue 7310 https://doi.org/10.1038/nature09343	journal	August 2010
N-terminal α-methylation of RCC1 is necessary for stable chromatin association and normal mitosis Chen, Ting; Muratore, Tara L.; Schaner-Tooley, Christine E. Nature Cell Biology, Vol. 9, Issue 5 https://doi.org/10.1038/ncb1572	journal	April 2007
α-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere Sathyan, Kizhakke M.; Fachinetti, Daniele; Foltz, Daniel R. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14678	journal	March 2017
DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression Cho, Min-Hyung; Park, Ji-Hye; Choi, Hee-Joo Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms8821	journal	July 2015
Design, synthesis, and kinetic analysis of potent protein N-terminal methyltransferase 1 inhibitors Zhang, Gang; Richardson, Stacie Lynn; Mao, Yunfei Organic & Biomolecular Chemistry, Vol. 13, Issue 14 https://doi.org/10.1039/C5OB00120J	journal	January 2015
Facile synthesis of SAM–peptide conjugates through alkyl linkers targeting protein N-terminal methyltransferase 1 Zhang, Gang; Huang, Rong RSC Advances, Vol. 6, Issue 8 https://doi.org/10.1039/C5RA20625A	journal	January 2016
Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state van Haren, Matthijs J.; Taig, Rebecca; Kuppens, Jilles Organic & Biomolecular Chemistry, Vol. 15, Issue 31 https://doi.org/10.1039/C7OB01357D	journal	January 2017
PRMT5 modulates the metabolic response to fasting signals Tsai, W. -W.; Niessen, S.; Goebel, N. Proceedings of the National Academy of Sciences, Vol. 110, Issue 22 https://doi.org/10.1073/pnas.1304602110	journal	May 2013
α-N-Methylation of Damaged DNA-binding Protein 2 (DDB2) and Its Function in Nucleotide Excision Repair Cai, Qian; Fu, Lijuan; Wang, Zi Journal of Biological Chemistry, Vol. 289, Issue 23 https://doi.org/10.1074/jbc.M114.558510	journal	June 2014
Kinetic Mechanism of Protein N-terminal Methyltransferase 1 Richardson, Stacie L.; Mao, Yunfei; Zhang, Gang Journal of Biological Chemistry, Vol. 290, Issue 18 https://doi.org/10.1074/jbc.M114.626846	journal	May 2015
Regulation of chromatin binding by a conformational switch in the tail of the Ran exchange factor RCC1 Hao, Yi; Macara, Ian G. The Journal of Cell Biology, Vol. 182, Issue 5 https://doi.org/10.1083/jcb.200803110	journal	September 2008
N-Trimethylalanine, a Novel Blocked N-Terminal Residue of Tetrahymena Histone H2B1 Nomoto, Minoru; Kyogoku, Yoshimasa; Iwai, Koichi The Journal of Biochemistry, Vol. 92, Issue 5 https://doi.org/10.1093/oxfordjournals.jbchem.a134096	journal	October 1982
Structural basis for substrate recognition by the human N-terminal methyltransferase 1 Dong, Cheng; Mao, Yunfei; Tempel, Wolfram Genes & Development, Vol. 29, Issue 22 https://doi.org/10.1101/gad.270611.115	journal	November 2015
Molecular basis for histone N-terminal methylation by NRMT1 Wu, Ruoxi; Yue, Yuan; Zheng, Xiangdong Genes & Development, Vol. 29, Issue 22 https://doi.org/10.1101/gad.270926.115	journal	November 2015
The methylated N-terminal tail of RCC1 is required for stabilisation of its interaction with chromatin by Ran in live cells Hitakomate, Ekarat; Hood, Fiona E.; Sanderson, Helen S. BMC Cell Biology, Vol. 11, Issue 1 https://doi.org/10.1186/1471-2121-11-43	journal	January 2010
Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis Bonsignore, Lindsay A.; Butler, Jill Sergesketter; Klinge, Carolyn M. Oncotarget, Vol. 6, Issue 14 https://doi.org/10.18632/oncotarget.3653	journal	March 2015

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Discovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1

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