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A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors
Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guani...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692381/ https://www.ncbi.nlm.nih.gov/pubmed/38045046 http://dx.doi.org/10.1016/j.apsb.2023.07.022 |
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author | Deng, Youchao Song, Xiaosheng Iyamu, Iredia D. Dong, Aiping Min, Jinrong Huang, Rong |
author_facet | Deng, Youchao Song, Xiaosheng Iyamu, Iredia D. Dong, Aiping Min, Jinrong Huang, Rong |
author_sort | Deng, Youchao |
collection | PubMed |
description | Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a “T-shaped” bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC(50) < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors. |
format | Online Article Text |
id | pubmed-10692381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-106923812023-12-03 A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors Deng, Youchao Song, Xiaosheng Iyamu, Iredia D. Dong, Aiping Min, Jinrong Huang, Rong Acta Pharm Sin B Original Article Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a “T-shaped” bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC(50) < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors. Elsevier 2023-12 2023-07-29 /pmc/articles/PMC10692381/ /pubmed/38045046 http://dx.doi.org/10.1016/j.apsb.2023.07.022 Text en © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Deng, Youchao Song, Xiaosheng Iyamu, Iredia D. Dong, Aiping Min, Jinrong Huang, Rong A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title | A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title_full | A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title_fullStr | A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title_full_unstemmed | A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title_short | A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors |
title_sort | unique binding pocket induced by a noncanonical sah mimic to develop potent and selective prmt inhibitors |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692381/ https://www.ncbi.nlm.nih.gov/pubmed/38045046 http://dx.doi.org/10.1016/j.apsb.2023.07.022 |
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