| Autor: |
Youchao Deng, Xiaosheng Song, Iredia D. Iyamu, Aiping Dong, Jinrong Min, Rong Huang |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Acta Pharmaceutica Sinica B, Vol 13, Iss 12, Pp 4893-4905 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-3835 |
| DOI: |
10.1016/j.apsb.2023.07.022 |
| Popis: |
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 (IC50 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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