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LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, With Antitumor Activity

LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, With Antitumor Activity

Zahid Q Bonday, Guillermo S Cortez, Michael J Grogan, Stephen Antonysamy, Ken Weichert, Wayne P Bocchinfuso, Fengling Li, Steven Kennedy, Binghui Li, Mary M Mader, Cheryl H Arrowsmith, Peter J Brown, Mohammad S Eram, etc.

ACS Med Chem Lett. 2018 Apr 23;9(7):612-617.

PMID: 30034588

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP2040291276	LLY-283		2040291-27-6	Price
IAR4243925	LLY-284			Price

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