Discovery of a novel small inhibitor RJ19 targeting to human Hsp90

IMR OpenIR

	Discovery of a novel small inhibitor RJ19 targeting to human Hsp90
其他题名	Discovery of a novel small inhibitor RJ19 targeting to human Hsp90
	Cao HuiLing 1; Lyu KaiKai 2; Liu Bin 3; Li Jian 4; He JianHua 4
	2017
发表期刊	NUCLEAR SCIENCE AND TECHNIQUES
ISSN	1001-8042
卷号	28 期号:10
摘要	Heat shock protein 90 (Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90(N) -RJ19 was determined by X-ray diffraction (resolution limit, 2.0 angstrom, PDB code 4L90). The crystal structure of Hsp90(N)-RJ19 was analyzed in detail and compared with that of native Hsp90(N), Hsp90(N)-ATP, and Hsp90(N) -GDM, respectively. It was indicated that RJ19 interacted with Hsp90(N) at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90(N) to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90(N)=-RJ19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90(N) provide a rational basis for the design and optimization of novel anticancer drugs.
其他摘要	Heat shock protein 90 (Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90(N) -RJ19 was determined by X-ray diffraction (resolution limit, 2.0 angstrom, PDB code 4L90). The crystal structure of Hsp90(N)-RJ19 was analyzed in detail and compared with that of native Hsp90(N), Hsp90(N)-ATP, and Hsp90(N) -GDM, respectively. It was indicated that RJ19 interacted with Hsp90(N) at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90(N) to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90(N)=-RJ19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90(N) provide a rational basis for the design and optimization of novel anticancer drugs.
关键词	ATP HYDROLYSIS PROTEIN CHAPERONE IDENTIFICATION BINDING DESIGN Heat shock protein 90 Drug target Inhibitor X-ray diffraction Complex crystal structure
收录类别	CSCD
语种	英语
资助项目	[National Natural Science Foundation of China] ; [Introduced talents]
CSCD记录号	CSCD:6090094
引用统计
文献类型	期刊论文
条目标识符	http://ir.imr.ac.cn/handle/321006/158118
专题	中国科学院金属研究所
作者单位	1.中国科学院地球环境研究所 2.中国科学院大学 3.Hubei Polytech University, Sch Med, Key Lab Prot Modificat & Tumor, Huangshi 435003, Peoples R China 4.中国科学院 5.中国科学院金属研究所 6.University Kentucky, Dept Mol & Cellular Biochem, Coll Med, Lexington, KY 40508 USA
推荐引用方式 GB/T 7714	Cao HuiLing,Lyu KaiKai,Liu Bin,et al. Discovery of a novel small inhibitor RJ19 targeting to human Hsp90[J]. NUCLEAR SCIENCE AND TECHNIQUES,2017,28(10).
APA	Cao HuiLing,Lyu KaiKai,Liu Bin,Li Jian,&He JianHua.(2017).Discovery of a novel small inhibitor RJ19 targeting to human Hsp90.NUCLEAR SCIENCE AND TECHNIQUES,28(10).
MLA	Cao HuiLing,et al."Discovery of a novel small inhibitor RJ19 targeting to human Hsp90".NUCLEAR SCIENCE AND TECHNIQUES 28.10(2017).