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

  • J Med Chem. 2025 Jan 23;68(2):1940-1955. doi: 10.1021/acs.jmedchem.4c02732.
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
Affiliations
  • 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.
PMID: 39787362 DOI: 10.1021/acs.jmedchem.4c02732
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.

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