10.1021/acs.jmedchem.6b01033.s001
Yudao Shen
Yudao
Shen
Magdalena M. Szewczyk
Magdalena M.
Szewczyk
Mohammad
S. Eram
Mohammad
S.
Eram
David Smil
David
Smil
H. Ümit Kaniskan
H. Ümit
Kaniskan
Renato Ferreira de Freitas
Renato
Ferreira de Freitas
Guillermo Senisterra
Guillermo
Senisterra
Fengling Li
Fengling
Li
Matthieu Schapira
Matthieu
Schapira
Peter
J. Brown
Peter
J.
Brown
Cheryl H. Arrowsmith
Cheryl H.
Arrowsmith
Dalia Barsyte-Lovejoy
Dalia
Barsyte-Lovejoy
Jing Liu
Jing
Liu
Masoud Vedadi
Masoud
Vedadi
Jian Jin
Jian
Jin
Discovery of a
Potent, Selective, and Cell-Active
Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein
Arginine Methyltransferase 6
American Chemical Society
2016
PRMT 4
Protein Arginine Methyltransferase 6 Well-characterized
SAR
chemical biology studies
protein arginine methyltransferases
chemical tools
PRMT 6
Protein Arginine Methyltransferase 4
049N
MS
2016-09-01 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_Potent_Selective_and_Cell-Active_Dual_Inhibitor_of_Protein_Arginine_Methyltransferase_4_and_Protein_Arginine_Methyltransferase_6/3830811
Well-characterized
selective inhibitors of protein arginine methyltransferases
(PRMTs) are invaluable chemical tools for testing biological and therapeutic
hypotheses. Based on <b>4</b>, a fragment-like inhibitor of
type I PRMTs, we conducted structure–activity relationship
(SAR) studies and explored three regions of this scaffold. The studies
led to the discovery of a potent, selective, and cell-active dual
inhibitor of PRMT4 and PRMT6, <b>17</b> (MS049). As compared
to <b>4</b>, <b>17</b> displayed much improved potency
for PRMT4 and PRMT6 in both biochemical and cellular assays. It was
selective for PRMT4 and PRMT6 over other PRMTs and a broad range of
other epigenetic modifiers and nonepigenetic targets. We also developed <b>46</b> (MS049N), which was inactive in biochemical and cellular
assays, as a negative control for chemical biology studies. Considering
possible overlapping substrate specificity of PRMTs, <b>17</b> and <b>46</b> are valuable chemical tools for dissecting specific
biological functions and dysregulation of PRMT4 and PRMT6 in health
and disease.