Download MendeleyA unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors.
Deng, Y., Song, X., Iyamu, I.D., Dong, A., Min, J., Huang, R.(2023) Acta Pharm Sin B 13: 4893-4905
- PubMed: 38045046
- DOI: https://doi.org/10.1016/j.apsb.2023.07.022
- Primary Citation of Related Structures:
8G2F, 8G2G, 8G2H, 8G2I - PubMed 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 (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.
Organizational Affiliation:
Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
