Discovery of Potent, Highly Selective, and Orally Bioavailable MTA Cooperative PRMT5 Inhibitors with Robust In Vivo Antitumor Activity

Meng Zhang ¹, Xiaoyu Ding ¹, Zhongying Cao ¹, Yilin Yang ¹, Xiao Ding ¹, Xin Cai ¹, Man Zhang ¹, Alex Aliper ², Feng Ren ¹, Hongfu Lu ¹, Alex Zhavoronkov ^{1 2 3}
1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.

2 Insilico Medicine AI Ltd, Masdar City, Abu Dhabi 145748, UAE.

3 Insilico Medicine Hong Kong Ltd, Hong Kong Science and Technology Park, Kowloon 999077, Hong Kong SAR, China.

ABSTRACT

Protein arginine methyltransferase 5 (PRMT5), which catalyzes the symmetric dimethylation of arginine residues on target proteins, plays a critical role in gene expression regulation, RNA processing, and signal transduction. Aberrant PRMT5 activity has been implicated in cancers and other diseases, making it a potential therapeutic target. Here, we report the discovery of a methylthioadenosine (MTA) cooperative PRMT5 inhibitor. Compound 20 exhibited strong antiproliferation activity in multiple MTAP-deleted cancer cell lines, excellent selectivity over MTAP wild-type cell lines, as well as satisfactory oral pharmacokinetic properties over various preclinical species. Notably, compound 20 demonstrated a dose-dependent reduction of symmetric dimethylarginine (SDMA) expression in the LU99 cell line and robust in vivo antitumor activity in the LU99 subcutaneous model.

Acknowledgments

We thank Dr. Yan Xu, Dr. Yu Gao, Dr. Likai Xia, Mr. Hai Chen, and all the chemists from WuXi AppTec who made contributions to the chemical synthesis support.

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