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Identification of Novel Inhibitors against Coactivator Associated Arginine Methyltransferase 1 Based on Virtual Screening and Biological Assays

Fei Ye, Weiyao Zhang, Wenchao Lu, Yiqian Xie, Hao Jiang, Jia Jin, Cheng Luo
2016 BioMed Research International  
In this study, together with structure-based virtual screening with biochemical assays, two compounds DC_C11 and DC_C66 were identified as novel inhibitors of CARM1.  ...  Overexpression of coactivator associated arginine methyltransferase 1 (CARM1), a protein arginine N-methyltransferase (PRMT) family enzyme, is associated with various diseases including cancers.  ...  Acknowledgments The authors gratefully acknowledge financial support from Zhejiang Province Natural Science Foundation (LQ14H 300003), The National Natural Science Foundation of China  ... 
doi:10.1155/2016/7086390 pmid:27872854 pmcid:PMC5107250 fatcat:ka5xtmxpnfbfhmy5hmszsfjjxy

Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations

Hongrui Tao, Xue Yan, Kongkai Zhu, Hua Zhang
2019 Chemical and pharmaceutical bulletin  
As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years.  ...  In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results.  ...  Conclusion Here, four new PRMT5 inhibitors with novel scaffolds were discovered by structure-based virtual screening, of which compounds 4 and 10 displayed the most potent activity with IC 50 values of  ... 
doi:10.1248/cpb.c18-00980 fatcat:7pr4cox75bbxlehdsq6npt3w5e

Targets in Epigenetics: Inhibiting the Methyl Writers of the Histone Code

Julianne M Yost, Ilia Korboukh, Feng Liu, Cen Gao, Jian Jin
2011 Current Chemical Genomics  
Growing evidence suggests that protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) are associated with the development of various human diseases, including cancer,  ...  In this review, we focus on the recent progress in the discovery of selective PKMT and PRMT inhibitors. A future perspective on developing methyltransferase inhibitors is also offered.  ...  ACKNOWLEDGEMENTS We thank the Carolina Partnership and the University Cancer Research Fund (UCRF) from the University of North Carolina at Chapel Hill for financial support.  ... 
doi:10.2174/1875397301005010072 pmid:21966347 pmcid:PMC3178896 fatcat:e7pmrv27yzeytjd3iy3srgj65e

Recent progress in developing selective inhibitors of protein methyltransferases

H. Ümit Kaniskan, Jian Jin
2017 Current Opinion in Chemical Biology  
inhibitors of protein lysine and arginine methyltransferases.  ...  Mounting evidence suggests that protein methyltrans•ferases (PMTs), which catalyze methylation of histone as well as non-histone •proteins, play aa crucial role in diverse biological pathways and human  ...  Acknowledgments This work was supported by Grant R01GM103893 (J.J.) and R01GM122749 (J.J.) from the National Institute of General Medical Sciences of the U.S. National Institutes of Health.  ... 
doi:10.1016/j.cbpa.2017.06.013 pmid:28662389 pmcid:PMC5624721 fatcat:2oo3sc7hiva2zgslqim4alcin4

Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-Based Virtual Screening

Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
2018 Frontiers in Pharmacology  
In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied.  ...  Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis.  ...  AUTHOR CONTRIBUTIONS XY, EL, and LL conceived the project. XY, EL, and QW designed the experiments. QW, JX, YL, JH, ZJ, and YW carried out the research and data analysis.  ... 
doi:10.3389/fphar.2018.00173 pmid:29545752 pmcid:PMC5838003 fatcat:oyyxm34dsjf7lhpkjdsqmfatzq

Pharmacophore-Based Virtual Screening and Biological Evaluation of Small Molecule Inhibitors for Protein Arginine Methylation

Juxian Wang, Limin Chen, Sarmistha Halder Sinha, Zhongjie Liang, Huifang Chai, Sakthivel Muniyan, Yu-Wei Chou, Chao Yang, Leilei Yan, You Feng, Keqin Kathy Li, Ming-Fong Lin (+3 others)
2012 Journal of Medicinal Chemistry  
We combined pharmacophore-based virtual screening methods with radioactive methylation assays, six hits were identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar  ...  Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism and signal transduction.  ...  ), Shanghai Committee of Science and Technology grants (10410703900) and the Chinese Academy of Sciences (XDA01040305) to CL and HJ.  ... 
doi:10.1021/jm300521m pmid:22928876 pmcid:PMC4150255 fatcat:gptoxx2lznhxdgf2gyzmavzl34

Computer-Aided Drug Design in Epigenetics

Wenchao Lu, Rukang Zhang, Hao Jiang, Huimin Zhang, Cheng Luo
2018 Frontiers in Chemistry  
, molecular dynamics simulations, quantum chemistry calculation, and 3D quantitative structure activity relationship that have been successfully applied in the design and discovery of epi-drugs and epi-probes  ...  Herein, we make a brief overview of major computational methods reported in the literature including druggability prediction, virtual screening, homology modeling, scaffold hopping, pharmacophore modeling  ...  Histone methyltransferases can be mainly divided into two categories based on their relative substrates: protein lysine methyltransferases and protein arginine N-methyltransferases .  ... 
doi:10.3389/fchem.2018.00057 pmid:29594101 pmcid:PMC5857607 fatcat:2q7nmu6ynvbzrdec4njjystoh4

Xenoestrogens Regulate the Activity of Arginine Methyltransferases

Donghang Cheng, Mark T. Bedford
2010 ChemBioChem  
We developed a cell-based reporter system for CARM1 activity, and showed that tamoxifen (IC 50 =30 µM) inhibits this PRMT.  ...  We termed these compounds AMIs (arginine methyltransferase inhibitors).  ...  Acknowledgments MT Bedford is supported by an institutional NIEHS center grant ES007784, ES015188 and DK062248. Salam Shaaban for generating the stable/inducible T-Rex-3XFlag-PABP1 cell line.  ... 
doi:10.1002/cbic.201000522 pmid:21243720 pmcid:PMC3142315 fatcat:x7f6k6fojbdz3o2njtujl3bjim

Methods for Activity Analysis of the Proteins that Regulate Histone Methylation

Amy M Quinn, Anton Simeonov
2011 Current Chemical Genomics  
The majority of histone demethylase and methyltransferase enzyme inhibitors have been discovered on the basis of their structural similarity to substrates or known inhibitors of enzymes with analogous  ...  These proteins are recognized as potential therapeutic targets for the treatment of diseases associated with epigenetic disruption; however, few inhibitors of their activity have been identified.  ...  ACKNOWLEDGEMENTS This research was supported in part by the Molecular Libraries Initiative of the NIH Roadmap for Medical Re-  ... 
doi:10.2174/1875397301005010095 pmid:21966349 pmcid:PMC3180180 fatcat:dsrgicl4czc4tpp5p3mteahjaq

Inhibitors of Protein Methyltransferases and Demethylases

H. Ümit Kaniskan, Michael L. Martini, Jian Jin
2017 Chemical Reviews  
Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade.  ...  Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated  ...  In 2016, Roatsch and co-workers described the identification of KDM4A inhibitors via virtual screening and follow-up optimization.  ... 
doi:10.1021/acs.chemrev.6b00801 pmid:28338320 pmcid:PMC5610952 fatcat:ifwczoutfndpljmpeqkyw2tsxm

Cell-based assays to support the profiling of small molecules with histone methyltransferase and demethylase modulatory activity

Natalia J. Martinez, Anton Simeonov
2015 Drug Discovery Today : Technologies  
Cell-based assays, on the contrary, provide a much more biologically relevant assessment of inhibitor effects on epigenetic marks.  ...  Several cell-based platforms have now been designed or adapted for HTMs and HDMs to support lead optimization and structure-activity-relationship (SAR) campaigns.  ...  A similar DELFIA approach that used fixed and permeabilized cells instead of cell lysates was previously employed to detect global H4R3 upon treatment with selected histone arginine methyltransferase inhibitors  ... 
doi:10.1016/j.ddtec.2015.10.004 pmid:26723887 pmcid:PMC4698313 fatcat:nu7gkirxlzdtjmuefxw2dft6tq

Chemical and biochemical approaches in the study of histone methylation and demethylation

Keqin Kathy Li, Cheng Luo, Dongxia Wang, Hualiang Jiang, Y. George Zheng
2012 Medicinal research reviews (Print)  
Discovery and design of selective organic inhibitors of histone methyltransferases and demethylases provide chemical probes to interrogate methylationmediated cellular pathways.  ...  ligation, mass spectrometry, biochemical methylation and demethylation assays, and inhibitor development.  ...  YGZ contributed to Chapters 1, 2, 5, 6, and 7 and overall organization of the paper.  ... 
doi:10.1002/mrr.20228 pmid:22777714 pmcid:PMC4129395 fatcat:hhujrdalnrbvfj6cchyonzje7i

Effects of a novel arginine methyltransferase inhibitor on T-helper cell cytokine production

Kevin Bonham, Saskia Hemmers, Yeon-Hee Lim, Dawn M. Hill, M. G. Finn, Kerri A. Mowen
2010 The FEBS Journal  
The protein arginine methyltransferase (PRMT) family of enzymes catalyzes the transfer of methyl groups from S-adenosylmethionine to the guanidino nitrogen atom of peptidylarginine to form monomethylarginine  ...  We created several less polar analogues of the specific PRMT inhibitor AMI-1, and one such compound was found to have improved PRMT inhibitory activity over the parent molecule.  ...  Sanja Arandjelovic for critical reading and review of the manuscript. This is manuscript # 20585 from TSRI. This work was partially supported by grants from NIAID AI067460-01  ... 
doi:10.1111/j.1742-4658.2010.07623.x pmid:20345902 pmcid:PMC2903848 fatcat:spvwnu6wcbf33nde2xycxgqlva

Selective Inhibitors of Protein Methyltransferases

H. Ümit Kaniskan, Kyle D. Konze, Jian Jin
2014 Journal of Medicinal Chemistry  
PMTs are divided into two categories: protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs).  ...  Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and human diseases.  ...  Activities of these DOT1L inhibitors in cell-based assays were not reported.  ... 
doi:10.1021/jm501234a pmid:25406853 pmcid:PMC4345896 fatcat:qwmdalzxirgtnjujabi5gfiy64

Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy [chapter]

Jakyung Yoo, Jose L.
2011 Drug Development - A Case Study Based Insight into Modern Strategies  
Ligand-based approaches use the structural information and biological activity data from a set of known active compounds to select promising candidates for experimental screening.  ...  Ligand-based virtual screening may be applied even if a single known-ligand has been identified through similarity-based screening.  ...  Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy, Drug Development -A Case Study Based Insight into Modern Strategies, Dr.  ... 
doi:10.5772/27742 fatcat:o642qlv7hzeuzgkvw7i52g2sni
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