Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)

Kaniskan, H. Ümit; Eram, Mohammad S.; Zhao, Kehao; Szewczyk, Magdalena M.; Yang, Xiaobao; Schmidt, Keith; Luo, Xiao; Xiao, Sean; Dai, Miao; He, Feng; Zang, Irene; Lin, Ying; Li, Fengling; Dobrovetsky, Elena; Smil, David; Min, Sun-Joon; Lin-Jones, Jennifer; Schapira, Matthieu; Atadja, Peter; Li, En; Barsyte-Lovejoy, Dalia; Arrowsmith, Cheryl H.; Brown, Peter J.; Liu, Feng; Yu, Zhengtian; Vedadi, Masoud; Jin, Jian

doi:10.1021/acs.jmedchem.7b01674

Title: Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)

Journal Article · Fri Dec 15 00:00:00 UTC 2017 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.7b01674 · OSTI ID:1570752

Kaniskan, H. Ümit ^[1]; Eram, Mohammad S. ^[2]; Zhao, Kehao ^[3]; Szewczyk, Magdalena M. ^[2]; Yang, Xiaobao ^[1]; Schmidt, Keith ^[1]; Luo, Xiao ^[3]; Xiao, Sean ^[3]; Dai, Miao ^[3]; He, Feng ^[3]; Zang, Irene ^[3]; Lin, Ying ^[3]; Li, Fengling ^[2]; Dobrovetsky, Elena ^[2]; Smil, David ^[2];

^[1]; Lin-Jones, Jennifer ^[4];

^[2]; Atadja, Peter ^[3]; Li, En ^[3] more »

Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Toronto, ON (Canada)
Novartis Inst. for Biomedical Research, Shanghai (China)
DiscoveRx Corporation, Fremont, CA (United States)
Soochow Univ., Suzhou (China)

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure–activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC₅₀ values: ~10–36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49–51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Natural Science Foundation of China (NNSFC); USDOE

OSTI ID:: 1570752

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 3 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (45)

Über aromatische Fluorverbindungen, I.: Ein neues Verfahren zu ihrer Darstellung Balz, Günther; Schiemann, Günther Berichte der deutschen chemischen Gesellschaft (A and B Series), Vol. 60, Issue 5 https://doi.org/10.1002/cber.19270600539	journal	May 1927
Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2 Eram, Mohammad S.; Kuznetsova, Ekaterina; Li, Fengling Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1850, Issue 9 https://doi.org/10.1016/j.bbagen.2015.05.013	journal	September 2015
Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity Zhu, Gui-Dong; Gong, Jianchun; Claiborne, Akiyo Bioorganic & Medicinal Chemistry Letters, Vol. 16, Issue 12 https://doi.org/10.1016/j.bmcl.2006.03.041	journal	June 2006
PRMT3 is essential for dendritic spine maturation in rat hippocampal neurons Miyata, Shingo; Mori, Yasutake; Tohyama, Masaya Brain Research, Vol. 1352 https://doi.org/10.1016/j.brainres.2010.07.033	journal	September 2010
New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro Park, Min-Jung; Kim, Dong-Il; Choi, Joo-Hee Cellular Signalling, Vol. 27, Issue 9 https://doi.org/10.1016/j.cellsig.2015.04.010	journal	September 2015
Protein Arginine Methylation in Mammals: Who, What, and Why Bedford, Mark T.; Clarke, Steven G. Molecular Cell, Vol. 33, Issue 1 https://doi.org/10.1016/j.molcel.2008.12.013	journal	January 2009
Activity-Based Protein Profiling of Protein Arginine Methyltransferase 1 Obianyo, Obiamaka; Causey, Corey P.; Jones, Justin E. ACS Chemical Biology, Vol. 6, Issue 10 https://doi.org/10.1021/cb2001473	journal	August 2011
Proteomic Dissection of the von Hippel–Lindau (VHL) Interactome Lai, Yanlai; Song, Meihua; Hakala, Kevin Journal of Proteome Research, Vol. 10, Issue 11 https://doi.org/10.1021/pr200642c	journal	November 2011
PRMT3 is a ribosomal protein methyltransferase that affects the cellular levels of ribosomal subunits Bachand, François; Silver, Pamela A. The EMBO Journal, Vol. 23, Issue 13 https://doi.org/10.1038/sj.emboj.7600265	journal	June 2004
DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo Singh, Vinita; Miranda, Tina Branscombe; Jiang, Wei Oncogene, Vol. 23, Issue 47 https://doi.org/10.1038/sj.onc.1208057	journal	August 2004
Ribosomal protein S2 is a substrate for mammalian PRMT3 (protein arginine methyltransferase 3) Swiercz, Rafal; Person, Maria D.; Bedford, Mark T. Biochemical Journal, Vol. 386, Issue 1 https://doi.org/10.1042/bj20041466	journal	February 2005
(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells Barsyte-Lovejoy, D.; Li, F.; Oudhoff, M. J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 35 https://doi.org/10.1073/pnas.1407358111	journal	August 2014
PRMT 3, a Type I Protein Arginine N-Methyltransferase That Differs from PRMT1 in Its Oligomerization, Subcellular Localization, Substrate Specificity, and Regulation Tang, Jie; Gary, Jonathan D.; Clarke, Steven Journal of Biological Chemistry, Vol. 273, Issue 27 https://doi.org/10.1074/jbc.273.27.16935	journal	July 1998
Trimethylation of Histone H3 Lysine 36 by Human Methyltransferase PRDM9 Protein Eram, Mohammad S.; Bustos, Susan P.; Lima-Fernandes, Evelyne Journal of Biological Chemistry, Vol. 289, Issue 17 https://doi.org/10.1074/jbc.m113.523183	journal	March 2014
Ribosomal Protein rpS2 Is Hypomethylated in PRMT3-deficient Mice Swiercz, Rafal; Cheng, Donghang; Kim, Daehoon Journal of Biological Chemistry, Vol. 282, Issue 23 https://doi.org/10.1074/jbc.m609778200	journal	June 2007
Promiscuous Modification of the Nuclear Poly(A)-binding Protein by Multiple Protein-arginine Methyltransferases Does Not Affect the Aggregation Behavior Fronz, Katharina; Otto, Silke; Kölbel, Knut Journal of Biological Chemistry, Vol. 283, Issue 29 https://doi.org/10.1074/jbc.m802329200	journal	July 2008
Human protein arginine methyltransferases in vivo - distinct properties of eight canonical members of the PRMT family Herrmann, F.; Pably, P.; Eckerich, C. Journal of Cell Science, Vol. 122, Issue 5 https://doi.org/10.1242/jcs.039933	journal	February 2009
Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors H., Arrowsmith, Cheryl; Aiping, Dong,; Matthieu, Schapira, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/9963-vj92	text	January 2013
PRMT3 Regulates Hepatic Lipogenesis Through Direct Interaction With LXRα Kim, Dong-il; Park, Min-jung; Lim, Seul-ki Diabetes, Vol. 64, Issue 1 https://doi.org/10.2337/db13-1394	journal	September 2014
A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3) Kaniskan, H. Ümit; Szewczyk, Magdalena M.; Yu, Zhengtian Angewandte Chemie International Edition, Vol. 54, Issue 17 https://doi.org/10.1002/anie.201412154	journal	February 2015
Über aromatische Fluorverbindungen, I.: Ein neues Verfahren zu ihrer Darstellung Balz, Günther; Schiemann, Günther Berichte der deutschen chemischen Gesellschaft (A and B Series), Vol. 60, Issue 5 https://doi.org/10.1002/cber.19270600539	journal	May 1927
Expression of nitric oxide related enzymes in coronary heart disease Chen, X.; Niroomand, F.; Liu, Z. Basic Research in Cardiology, Vol. 101, Issue 4 https://doi.org/10.1007/s00395-006-0592-5	journal	May 2006
Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2 Eram, Mohammad S.; Kuznetsova, Ekaterina; Li, Fengling Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1850, Issue 9 https://doi.org/10.1016/j.bbagen.2015.05.013	journal	September 2015
Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity Zhu, Gui-Dong; Gong, Jianchun; Claiborne, Akiyo Bioorganic & Medicinal Chemistry Letters, Vol. 16, Issue 12 https://doi.org/10.1016/j.bmcl.2006.03.041	journal	June 2006
PRMT3 is essential for dendritic spine maturation in rat hippocampal neurons Miyata, Shingo; Mori, Yasutake; Tohyama, Masaya Brain Research, Vol. 1352 https://doi.org/10.1016/j.brainres.2010.07.033	journal	September 2010
New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro Park, Min-Jung; Kim, Dong-Il; Choi, Joo-Hee Cellular Signalling, Vol. 27, Issue 9 https://doi.org/10.1016/j.cellsig.2015.04.010	journal	September 2015
Protein Arginine Methylation in Mammals: Who, What, and Why Bedford, Mark T.; Clarke, Steven G. Molecular Cell, Vol. 33, Issue 1 https://doi.org/10.1016/j.molcel.2008.12.013	journal	January 2009
An Allosteric Inhibitor of Protein Arginine Methyltransferase 3 Siarheyeva, Alena; Senisterra, Guillermo; Allali-Hassani, Abdellah Structure, Vol. 20, Issue 8 https://doi.org/10.1016/j.str.2012.06.001	journal	August 2012
Activity-Based Protein Profiling of Protein Arginine Methyltransferase 1 Obianyo, Obiamaka; Causey, Corey P.; Jones, Justin E. ACS Chemical Biology, Vol. 6, Issue 10 https://doi.org/10.1021/cb2001473	journal	August 2011
Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors Liu, Feng; Li, Fengling; Ma, Anqi Journal of Medicinal Chemistry, Vol. 56, Issue 5 https://doi.org/10.1021/jm3018332	journal	February 2013
Proteomic Dissection of the von Hippel–Lindau (VHL) Interactome Lai, Yanlai; Song, Meihua; Hakala, Kevin Journal of Proteome Research, Vol. 10, Issue 11 https://doi.org/10.1021/pr200642c	journal	November 2011
PRMT3 is a ribosomal protein methyltransferase that affects the cellular levels of ribosomal subunits Bachand, François; Silver, Pamela A. The EMBO Journal, Vol. 23, Issue 13 https://doi.org/10.1038/sj.emboj.7600265	journal	June 2004
DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo Singh, Vinita; Miranda, Tina Branscombe; Jiang, Wei Oncogene, Vol. 23, Issue 47 https://doi.org/10.1038/sj.onc.1208057	journal	August 2004
Ribosomal protein S2 is a substrate for mammalian PRMT3 (protein arginine methyltransferase 3) Swiercz, Rafal; Person, Maria D.; Bedford, Mark T. Biochemical Journal, Vol. 386, Issue 1 https://doi.org/10.1042/BJ20041466	journal	February 2005
(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells Barsyte-Lovejoy, D.; Li, F.; Oudhoff, M. J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 35 https://doi.org/10.1073/pnas.1407358111	journal	August 2014
PRMT 3, a Type I Protein Arginine N-Methyltransferase That Differs from PRMT1 in Its Oligomerization, Subcellular Localization, Substrate Specificity, and Regulation Tang, Jie; Gary, Jonathan D.; Clarke, Steven Journal of Biological Chemistry, Vol. 273, Issue 27 https://doi.org/10.1074/jbc.273.27.16935	journal	July 1998
Trimethylation of Histone H3 Lysine 36 by Human Methyltransferase PRDM9 Protein Eram, Mohammad S.; Bustos, Susan P.; Lima-Fernandes, Evelyne Journal of Biological Chemistry, Vol. 289, Issue 17 https://doi.org/10.1074/jbc.M113.523183	journal	March 2014
SET-mediated Promoter Hypoacetylation Is a Prerequisite for Coactivation of the Estrogen-responsive pS2 Gene by PRMT1 Wagner, Sabine; Weber, Susanne; Kleinschmidt, Markus A. Journal of Biological Chemistry, Vol. 281, Issue 37 https://doi.org/10.1074/jbc.M605172200	journal	September 2006
Ribosomal Protein rpS2 Is Hypomethylated in PRMT3-deficient Mice Swiercz, Rafal; Cheng, Donghang; Kim, Daehoon Journal of Biological Chemistry, Vol. 282, Issue 23 https://doi.org/10.1074/jbc.M609778200	journal	June 2007
Promiscuous Modification of the Nuclear Poly(A)-binding Protein by Multiple Protein-arginine Methyltransferases Does Not Affect the Aggregation Behavior Fronz, Katharina; Otto, Silke; Kölbel, Knut Journal of Biological Chemistry, Vol. 283, Issue 29 https://doi.org/10.1074/jbc.M802329200	journal	July 2008
Human PDCD2L Is an Export Substrate of CRM1 That Associates with 40S Ribosomal Subunit Precursors Landry-Voyer, Anne-Marie; Bilodeau, Sarah; Bergeron, Danny Molecular and Cellular Biology, Vol. 36, Issue 24 https://doi.org/10.1128/MCB.00303-16	journal	December 2016
Fluorescence-Based Methods for Screening Writers and Readers of Histone Methyl Marks Allali-Hassani, Abdellah; Wasney, Gregory A.; Siarheyeva, Alena Journal of Biomolecular Screening, Vol. 17, Issue 1 https://doi.org/10.1177/1087057111422256	journal	October 2011
Human protein arginine methyltransferases in vivo - distinct properties of eight canonical members of the PRMT family Herrmann, F.; Pably, P.; Eckerich, C. Journal of Cell Science, Vol. 122, Issue 5 https://doi.org/10.1242/jcs.039933	journal	February 2009
Hsp70 Chaperones and Type I PRMTs Are Sequestered at Intranuclear Inclusions Caused by Polyalanine Expansions in PABPN1 Tavanez, João Paulo; Bengoechea, Rocio; Berciano, Maria T. PLoS ONE, Vol. 4, Issue 7 https://doi.org/10.1371/journal.pone.0006418	journal	July 2009
PRMT3 Regulates Hepatic Lipogenesis Through Direct Interaction With LXRα Kim, Dong-il; Park, Min-jung; Lim, Seul-ki Diabetes, Vol. 64, Issue 1 https://doi.org/10.2337/db13-1394	journal	September 2014

Cited By (7)

The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting Pirola, Luciano; Ciesielski, Oskar; Balcerczyk, Aneta Cancers, Vol. 10, Issue 8 https://doi.org/10.3390/cancers10080268	journal	August 2018
Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor Ferreira de Freitas, Renato; Ivanochko, Danton; Schapira, Matthieu Molecules, Vol. 24, Issue 24 https://doi.org/10.3390/molecules24244492	journal	December 2019
Colon cancer stemness as a reversible epigenetic state: Implications for anticancer therapies Vincent, Audrey; Ouelkdite-Oumouchal, Aïcha; Souidi, Mouloud World Journal of Stem Cells, Vol. 11, Issue 11 https://doi.org/10.4252/wjsc.v11.i11.920	journal	November 2019
Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level Tewary, Sunil Kumar; Zheng, Y. George; Ho, Meng-Chiao Cellular and Molecular Life Sciences, Vol. 76, Issue 15 https://doi.org/10.1007/s00018-019-03145-x	journal	May 2019
Targeting protein methylation: from chemical tools to precision medicines Dilworth, David; Barsyte-Lovejoy, Dalia Cellular and Molecular Life Sciences, Vol. 76, Issue 15 https://doi.org/10.1007/s00018-019-03147-9	journal	May 2019
The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting Pirola, Luciano; Ciesielski, Oskar; Balcerczyk, Aneta Cancers, Vol. 10, Issue 8 https://doi.org/10.3390/cancers10080268	journal	August 2018
Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor Ferreira de Freitas, Renato; Ivanochko, Danton; Schapira, Matthieu Molecules, Vol. 24, Issue 24 https://doi.org/10.3390/molecules24244492	journal	December 2019

Similar Records

A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases

Journal Article · Tue Nov 24 00:00:00 UTC 2015 · ACS Chemical Biology · OSTI ID:1243125

Eram, Mohammad S.; Shen, Yudao; Szewczyk, Magdalena M.; +16 more

Identification of a peptide inhibitor for the histone methyltransferase WHSC1

Journal Article · Wed May 09 00:00:00 UTC 2018 · PLoS ONE · OSTI ID:1466056

Morrison, Michael J.; Boriack-Sjodin, P. Ann; Swinger, Kerren K.; +12 more

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

Journal Article · Wed Jan 10 00:00:00 UTC 2018 · Journal of Medicinal Chemistry · OSTI ID:1431360

Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling; +7 more

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
amides
inhibitors
pyrrolidines
reaction products
substituents

Title: Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)

Citation Formats

References (45)

Cited By (7)

Similar Records

Related Subjects