Meng Zhang, Xiaoyu Ding, Zhongying Cao, Yilin Yang, Xiao Ding, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Hongfu Lu* and Alex Zhavoronkov*,
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Discovery of Potent, Highly Selective, and Orally Bioavailable MTA Cooperative PRMT5 Inhibitors with Robust In Vivo Antitumor Activity
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.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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