LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity
Protein arginine methyltransferase 5 (PRMT5) is really a type II arginine methyltransferase that catalyzes the development of symmetric dimethylarginine in many nuclear and cytoplasmic proteins. Even though the cellular functions of PRMT5 haven’t been fully unraveled, it’s been implicated in many cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in many tissues and it is expression continues to be proven to become elevated in a number of cancers including cancer of the breast, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and portrayal of the novel and selective PRMT5 inhibitor with potent in vitro as well as in vivo activity. Compound 1 (also known as LLY-283) inhibited PRMT5 enzymatic activity in vitro as well as in cells with IC50 of twenty-two ± 3 and 25 ± 1 nM, correspondingly, while its diastereomer, compound 2 (also known as LLY-284), was significantly less active. Compound 1 also demonstrated antitumor activity in mouse xenografts when dosed orally and may serve as a great probe molecule for comprehending the biological purpose of PRMT5 in normal and cancer cells.