A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors.
10.1016/j.apsb.2023.07.022
- Author:
Youchao DENG
1
;
Xiaosheng SONG
2
;
Iredia D IYAMU
1
;
Aiping DONG
2
;
Jinrong MIN
2
;
Rong HUANG
1
Author Information
1. Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
2. Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
- Publication Type:Journal Article
- Keywords:
Benzyl urea;
Crystal structure;
Homocysteine binding pocket;
Noncanonical SAH mimic;
PRMTs;
Structure based inhibitor design
- From:
Acta Pharmaceutica Sinica B
2023;13(12):4893-4905
- CountryChina
- Language:English
-
Abstract:
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 < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.
