Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors

doi:10.1016/j.bmcl.2018.10.026

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	Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors
	Zhu, Kongkai 1,2; Song, Jia-Li 1; Tao, Hong-Rui 1; Cheng, Zhi-Qiang 1; Jiang, Cheng-Shi 1; Zhang, Hua 1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2018-12-15
卷号	28 期号:23-24 页码:3693-3699
关键词	Pharmacophore combination Isoquinoline PRMT5 inhibitor Molecular docking Molecular dynamics simulation
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2018.10.026
文献子类	Article
英文摘要	Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as a promising therapeutic target for human cancer. Up to now, two small molecule PRMT5 inhibitors has been put into phase I clinical trial. In the present study, a series of candidate molecules were designed by combining key pharmacophores of formerly reported PRMT5 inhibitors. The in vitro PRMT5 inhibitory testing of compound 4b14 revealed an IC50 of 2.71 mu M, exhibiting high selectivity over PRMT1 and PRMT4 (> 70-fold selective). As expected, 4b14 exhibited potent anti-proliferative activity against a panel of leukemia and lymphoma cells, including MV4-11, Pfeiffer, SU-DHL-4 and KARPAS-422. Besides, 4b14 showed significant cell cycle arrest and apoptosis-inducing effects, as well as reduced the cellular symmetric arginine dimethylation level of SmD3 protein. Finally, affinity profiling analysis indicated that hydrophobic interactions, pi-pi stacking and cation-pi actions made the major contributions to the overall binding affinity. This scaffold provides a new chemical template for further development of better lead compounds targeting PRMT5.
资助项目	National Natural Science Foundation of China[81803438] ; National Natural Science Foundation of China[21672082] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; Shandong Provincial Natural Science Foundation[JQ201721] ; Shandong Key Development Project[2016GSF201209] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] ; Programs Foundation of University of Jinan[160100202]
WOS关键词	SELECTIVE INHIBITOR ; IDENTIFICATION ; METHYLATION ; GROWTH
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000453232500022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279466]
专题	药物发现与设计中心
通讯作者	Jiang, Cheng-Shi; Zhang, Hua
作者单位	1.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Kongkai,Song, Jia-Li,Tao, Hong-Rui,et al. Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2018,28(23-24):3693-3699.
APA	Zhu, Kongkai,Song, Jia-Li,Tao, Hong-Rui,Cheng, Zhi-Qiang,Jiang, Cheng-Shi,&Zhang, Hua.(2018).Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,28(23-24),3693-3699.
MLA	Zhu, Kongkai,et al."Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 28.23-24(2018):3693-3699.