A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

• Published in: Acta pharmaceutica Sinica. B Vol. 13; no. 12; pp. 4893 - 4905
• Main Authors: Deng, Youchao, Song, Xiaosheng, Iyamu, Iredia D., Dong, Aiping, Min, Jinrong, Huang, Rong
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2023; Elsevier
• Subjects: Benzyl urea; Crystal structure; Homocysteine binding pocket; Noncanonical SAH mimic; Original; PRMTs; Structure based inhibitor design; Benzyl urea; Structure based inhibitor design; Noncanonical SAH mimic; Homocysteine binding pocket; PRMTs; Crystal structure
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2023.07.022

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. A noncanonical SAH surrogate YD1113 can induce a unique binding pocket in PRMT3/4, is a versatile fragment to increase the potency and selectivity of the reported PRMT bisubstrate inhibitors. [Display omitted]