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J Med Chem. 2017 Nov 9;60(21):8888-8905. doi: 10.1021/acs.jmedchem.7b01134. Epub 2017 Oct 27.

Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation.

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College of Life Sciences, Zhejiang Sci-Tech University , Hangzhou 310018, China.
Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
School of Life Science and Technology, ShanghaiTech University , 100 Haike Road, Shanghai 201210, China.
Shanghai ChemPartner Co., Ltd. , #5 Building, 998, Halei Road, Shanghai 201203, China.
College of Chemical and Environmental Engineering, Shanghai Institute of Technology , Shanghai 210032, China.


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.

[Indexed for MEDLINE]

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