A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes
Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/6/854 |
| _version_ | 1797530964809744384 |
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| author | Iredia D. Iyamu Ayad A. Al-Hamashi Rong Huang |
| author_facet | Iredia D. Iyamu Ayad A. Al-Hamashi Rong Huang |
| author_sort | Iredia D. Iyamu |
| collection | DOAJ |
| description | Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC<sub>50</sub>) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC<sub>50</sub> = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT. |
| first_indexed | 2024-03-10T10:37:26Z |
| format | Article |
| id | doaj.art-c59f26d06ce1427683212f1a6b6c56db |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T10:37:26Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c59f26d06ce1427683212f1a6b6c56db2023-11-21T23:12:59ZengMDPI AGBiomolecules2218-273X2021-06-0111685410.3390/biom11060854A Pan-Inhibitor for Protein Arginine Methyltransferase Family EnzymesIredia D. Iyamu0Ayad A. Al-Hamashi1Rong Huang2Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USADepartment of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USADepartment of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USAProtein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC<sub>50</sub>) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC<sub>50</sub> = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT.https://www.mdpi.com/2218-273X/11/6/854protein arginine methyltransferasesinhibitormethyltransferasecompetitive inhibitor |
| spellingShingle | Iredia D. Iyamu Ayad A. Al-Hamashi Rong Huang A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes Biomolecules protein arginine methyltransferases inhibitor methyltransferase competitive inhibitor |
| title | A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes |
| title_full | A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes |
| title_fullStr | A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes |
| title_full_unstemmed | A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes |
| title_short | A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes |
| title_sort | pan inhibitor for protein arginine methyltransferase family enzymes |
| topic | protein arginine methyltransferases inhibitor methyltransferase competitive inhibitor |
| url | https://www.mdpi.com/2218-273X/11/6/854 |
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