TY - JOUR
T1 - Development of Potent Type i Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation
AU - Wang, Chen
AU - Jiang, Hao
AU - Jin, Jia
AU - Xie, Yiqian
AU - Chen, Zhifeng
AU - Zhang, Hao
AU - Lian, Fulin
AU - Liu, Yu Chih
AU - Zhang, Chenhua
AU - Ding, Hong
AU - Chen, Shijie
AU - Zhang, Naixia
AU - Zhang, Yuanyuan
AU - Jiang, Hualiang
AU - Chen, Kaixian
AU - Ye, Fei
AU - Yao, Zhiyi
AU - Luo, Cheng
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N1-(2-((2-chlorophenyl)thio)benzyl)-N1-methylethane-1,2-diamine (28d, DCPR049-12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dimethylation levels. Serving as an effective inhibitor, 28d demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present 28d as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.
AB - Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N1-(2-((2-chlorophenyl)thio)benzyl)-N1-methylethane-1,2-diamine (28d, DCPR049-12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dimethylation levels. Serving as an effective inhibitor, 28d demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present 28d as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.
UR - https://www.scopus.com/pages/publications/85033378303
U2 - 10.1021/acs.jmedchem.7b01134
DO - 10.1021/acs.jmedchem.7b01134
M3 - 文章
C2 - 29019697
AN - SCOPUS:85033378303
SN - 0022-2623
VL - 60
SP - 8888
EP - 8905
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -
