6CKC

Structure of PRMT5:MEP50 in complex with LLY-283, a potent and selective inhibitor of PRMT5, with antitumor activity

Summary for 6CKC

• Entry DOI: 10.2210/pdb6ckc/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, 7-[(5R)-5-C-phenyl-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 111506.93

Authors

Antonysamy, S. (deposition date: 2018-02-27, release date: 2018-05-16, Last modification date: 2024-03-13)

Primary citation

Bonday, Z.Q.,Cortez, G.S.,Grogan, M.J.,Antonysamy, S.,Weichert, K.,Bocchinfuso, W.P.,Li, F.,Kennedy, S.,Li, B.,Mader, M.M.,Arrowsmith, C.H.,Brown, P.J.,Eram, M.S.,Szewczyk, M.M.,Barsyte-Lovejoy, D.,Vedadi, M.,Guccione, E.,Campbell, R.M.
LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.
ACS Med Chem Lett, 9:612-617, 2018

PubMed 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 and activity. Compound (also called LLY-283) inhibited PRMT5 enzymatic activity and in cells with IC of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound (also called LLY-284), was much less active. Compound 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.

PubMed: 30034588
DOI: 10.1021/acsmedchemlett.8b00014

Experimental method

X-RAY DIFFRACTION (2.8 Å)