Nuclear Science and Techniques

《核技术》(英文版) ISSN 1001-8042 CN 31-1559/TL     2019 Impact factor 1.556

Nuclear Science and Techniques ›› 2017, Vol. 28 ›› Issue (10): 148 doi: 10.1007/s41365-017-0300-1


Discovery of a novel small inhibitor RJ19 targeting to human Hsp90

Hui-Ling Cao 1 , Kai-Kai Lyu 2 , Bin Liu 3 , Jian Li 4,5,6 , Jian-Hua He 4   

  1. 1 Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an 710021, China
    2 University of Chinese Academy of Sciences, Beijing 100049, China
    3 Key Laboratory of Protein Modification and Tumor, Hubei Polytechnic University School of Medicine, Huangshi 435003, China
    4 Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201204, China
    5 Biotech and Biomedicine Science Co. Ltd., Shenyang 110000, China
    6 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40508, USA
  • Contact: Jian Li
  • Supported by:

    This work was supported by the National Natural Science Foundation of China (Nos. 31401185 and 81402850) and the Introduced talents Foundation of Xi’an Medical University (No. 2015 RCYJ 01).

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Hui-Ling Cao, Kai-Kai Lyu, Bin Liu, Jian Li, Jian-Hua He. Discovery of a novel small inhibitor RJ19 targeting to human Hsp90.Nuclear Science and Techniques, 2017, 28(10): 148     doi: 10.1007/s41365-017-0300-1


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 Hsp90N–RJ19 was determined by X-ray diffraction (resolution limit, 2.0 A , PDB code 4L90). The crystal structure of Hsp90N–RJ19 was analyzed in detail and compared with that of native Hsp90N, Hsp90N-ATP, and Hsp90N-GDM, respectively. It was indicated that RJ19 interacted with Hsp90N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90N 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 Hsp90N–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 Hsp90N provide a rational basis for the design and optimization of novel anticancer drugs.

Key words: Heat shock protein 90, Drug target, Inhibitor, X-ray diffraction, Complex crystal structure