Discovery of Non-ATP-Competitive Inhibitors of Polo-like Kinase1

doi:10.1002/cmdc.201600051

CORC > 北京大学 > 化学与分子工程学院

	Discovery of Non-ATP-Competitive Inhibitors of Polo-like Kinase1
	Yun, Taikangxiang ; Qin, Tan ; Liu, Ying ; Lai, Luhua
刊名	CHEMMEDCHEM
	2016
关键词	inhibitors kinase domain non-ATP binding site polo-like kinase1 virtual screening 1 PLK1 INHIBITORS P38 MAP KINASE CANCER-THERAPY BINDING-SITE BOX DOMAIN PROTEIN POLO-LIKE-KINASE-1 IDENTIFICATION APOPTOSIS DESIGN
DOI	10.1002/cmdc.201600051
英文摘要	Polo-like kinase1 (Plk1) is an evolutionarily conserved serine/threonine kinase, and its N-terminal kinase domain (KD) controls cell signaling through phosphorylation. Inhibitors of Plk1 are potential anticancer drugs. Most known Plk1 KD inhibitors are ATP-competitive compounds, which may suffer from low selectivity. In this study we discovered novel non-ATP-competitive Plk1 KD inhibitors by virtual screening and experimental studies. Potential binding sites in Plk1 KD were identified by using the protein binding site detection program Cavity. The identified site was subjected to molecular-docking-based virtual screening. The activities of top-ranking compounds were evaluated by invitro enzyme assay with full-length Plk1 and direct binding assay with Plk1 KD. Several compounds showed inhibitory activity, and the most potent was found to be 3-((2-oxo-2-(thiophen-2-yl)ethyl)thio)-6-(pyridin-3-ylmethyl)-1,2,4-triazin-5(4H)-one (compound 4) with an IC50 value of 13.1 +/- 1.7m. Our work provides new insight into the design of kinase inhibitors that target non-ATP binding sites.; Ministry of Science and Technology of China [2012AA020308]; National Natural Science Foundation of China [91313302, 21573012]; SCI(E); PubMed; ARTICLE; liuying@pku.edu.cn; lhlai@pku.edu.cn; 7; 713-717; 11
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/434189]
专题	化学与分子工程学院生命科学学院
推荐引用方式 GB/T 7714	Yun, Taikangxiang,Qin, Tan,Liu, Ying,et al. Discovery of Non-ATP-Competitive Inhibitors of Polo-like Kinase1[J]. CHEMMEDCHEM,2016.
APA	Yun, Taikangxiang,Qin, Tan,Liu, Ying,&Lai, Luhua.(2016).Discovery of Non-ATP-Competitive Inhibitors of Polo-like Kinase1.CHEMMEDCHEM.
MLA	Yun, Taikangxiang,et al."Discovery of Non-ATP-Competitive Inhibitors of Polo-like Kinase1".CHEMMEDCHEM (2016).