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Design and Synthesis of Chemical Probes for Epigenetic Modification Enzymes...
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Design and Synthesis of Chemical Probes for Epigenetic Modification Enzymes and Proteins

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 6354

Special Issue Editor

Prof. Dr. Yana Cen

E-Mail Website
Guest Editor
1. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA
2. Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA
Interests: epigenetics; sirtuins; chemical biology

Special Issue Information

Dear Colleagues,

The last few decades have witnessed the tremendous progress of epigenetics. The ever-growing epigenetic landscape is tightly and precisely regulated by a group of epigenetics modification enzymes and proteins, many of which have been proposed as potential therapeutic targets for the treatment of diseases such as cancer, neurodegeneration, and metabolic disorders. Innovative chemical approaches are highly sought after for a better understanding of the biological functions of these enzymes and proteins. This Special Issue will provide a broad overview of the most recent progress in the discovery, design, and synthesis of novel chemical probes for epigenetic modifying enzymes and proteins. Contributions (including full papers, communications, and reviews) that report the development of new methodologies, small molecule probes, or techniques to reveal the physiological relevance of abovementioned targets are welcome.

Prof. Dr. Yana Cen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Epigenetics
  • Synthesis
  • Medicinal chemistry
  • Chemical biology
  • Chemical approach
  • Chemical tool
  • Photoaffinity probe
  • PROTAC
  • Activity-base probe
  • Fragment-based drug discovery
  • Structure–activity relationship (SAR)

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Published Papers (2 papers)

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Research

17 pages, 2322 KiB  
Article
Synthesis and Activity of Triazole-Adenosine Analogs as Protein Arginine Methyltransferase 5 Inhibitors
by Tyler Brown, Mengtong Cao and Y. George Zheng
Molecules 2022, 27(12), 3779; https://doi.org/10.3390/molecules27123779 - 11 Jun 2022
Cited by 2 | Viewed by 2729
Abstract
Protein arginine methyltransferase 5 (PRMT5) is an attractive molecular target in anticancer drug discovery due to its extensive involvement in transcriptional control, RNA processing, and other cellular pathways that are causally related to tumor initiation and progression. In recent years, various compounds have [...] Read more.
Protein arginine methyltransferase 5 (PRMT5) is an attractive molecular target in anticancer drug discovery due to its extensive involvement in transcriptional control, RNA processing, and other cellular pathways that are causally related to tumor initiation and progression. In recent years, various compounds have been screened or designed to target either the substrate- or cofactor-binding site of PRMT5. To expand the diversity of chemotypes for inhibitory binding to PRMT5 and other AdoMet-dependent methyltransferases, in this work, we designed a series of triazole-containing adenosine analogs aimed at targeting the cofactor-binding site of PRMT5. Triazole rings have commonly been utilized in drug discovery due to their ease of synthesis and functionalization as bioisosteres of amide bonds. Herein, we utilized the electronic properties of the triazole ring as a novel way to specifically target the cofactor-binding site of PRMT5. A total of about 30 compounds were synthesized using the modular alkyne-azide cycloaddition reaction. Biochemical tests showed that these compounds exhibited inhibitory activity of PRMT5 at varying degrees and several showed single micromolar potency, with clear selectivity for PRMT5 over PRMT1. Docking-based structural analysis showed that the triazole ring plays a key role in binding to the characteristic residue Phe327 in the active pocket of PRMT5, explaining the compounds’ selectivity for this type-II enzyme. Overall, this work provides new structure–activity relationship information on the design of AdoMet analogs for selective inhibition of PRMT5. Further structural optimization work will further improve the potency of the top leads. Full article
(This article belongs to the Special Issue Design and Synthesis of Chemical Probes for Epigenetic Modification Enzymes and Proteins)
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10 pages, 4169 KiB  
Article
Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1
by Guangping Dong, Iredia D. Iyamu, Jonah Z. Vilseck, Dongxing Chen and Rong Huang
Molecules 2022, 27(4), 1381; https://doi.org/10.3390/molecules27041381 - 18 Feb 2022
Cited by 6 | Viewed by 2719
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 [...] Read more.
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 (IC50 = 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 IC50 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. Full article
(This article belongs to the Special Issue Design and Synthesis of Chemical Probes for Epigenetic Modification Enzymes and Proteins)
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