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PDBsum entry 6ckc
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References listed in PDB file
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Key reference
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Title
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Lly-283, A potent and selective inhibitor of arginine methyltransferase 5, Prmt5, With antitumor activity.
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Authors
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Z.Q.Bonday,
G.S.Cortez,
M.J.Grogan,
S.Antonysamy,
K.Weichert,
W.P.Bocchinfuso,
F.Li,
S.Kennedy,
B.Li,
M.M.Mader,
C.H.Arrowsmith,
P.J.Brown,
M.S.Eram,
M.M.Szewczyk,
D.Barsyte-Lovejoy,
M.Vedadi,
E.Guccione,
R.M.Campbell.
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Ref.
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ACS Med Chem Lett, 2018,
9,
612-617.
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PubMed id
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Abstract
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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.
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