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Updated: Feb 7, 2026
Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
Published on: August 7, 2021
LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity
Zahid Q Bonday1, Guillermo S Cortez1, Michael J Grogan1
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.
Insights
Researchers developed a novel inhibitor, LLY-283, targeting Protein Arginine Methyltransferase 5 (PRMT5). This selective compound shows potent in vitro and in vivo antitumor activity, offering a new tool for cancer research.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a key enzyme involved in symmetric dimethylarginine formation.
- PRMT5 plays roles in RNA processing, signal transduction, and transcriptional regulation.
- Elevated PRMT5 expression is linked to various cancers, including breast, gastric, glioblastoma, and lymphoma.
Purpose of the Study:
- To identify and characterize a novel, selective inhibitor of PRMT5.
- To evaluate the in vitro and in vivo efficacy of the identified inhibitor.
- To establish a chemical probe for studying PRMT5 functions in normal and cancerous cells.
Main Methods:
- Enzymatic activity assays to determine IC50 values for PRMT5 inhibition.
- Cell-based assays to assess PRMT5 inhibition in cellular contexts.
- In vivo studies using mouse xenograft models to evaluate antitumor activity.
Main Results:
- Compound 1 (LLY-283) potently inhibited PRMT5 enzymatic activity with an IC50 of 22 ± 3 nM in vitro and 25 ± 1 nM in cells.
- Its diastereomer, compound 2 (LLY-284), exhibited significantly lower activity.
- Compound 1 demonstrated oral antitumor activity in mouse xenografts.
Conclusions:
- A novel and selective PRMT5 inhibitor, LLY-283, has been identified and characterized.
- LLY-283 exhibits potent in vitro and in vivo activity, including antitumor effects.
- LLY-283 serves as a valuable probe for investigating PRMT5's biological roles in health and disease.
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