1. LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity
- Author
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Steven Kennedy, Dalia Barsyte-Lovejoy, Zahid Quyoom Bonday, Ken Weichert, Wayne P. Bocchinfuso, Grogan Michael John, Mary M. Mader, Masoud Vedadi, Robert M. Campbell, Cheryl H. Arrowsmith, Cortez Guillermo S, Fengling Li, Stephen Antonysamy, Mohammad S. Eram, Ernesto Guccione, Binghui Li, Peter Brown, and Magdalena M. Szewczyk
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Methyltransferase ,Protein arginine methyltransferase 5 ,Organic Chemistry ,Methylation ,Biochemistry ,Molecular biology ,In vitro ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Enzyme ,chemistry ,In vivo ,030220 oncology & carcinogenesis ,Drug Discovery ,Transcriptional regulation ,Signal transduction - Abstract
[Image: see text] 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 IC(50) 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.
- Published
- 2018