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    Home > Xu Yong, research group of Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences: new progress in the field of anti prostate cancer drugs

    Xu Yong, research group of Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences: new progress in the field of anti prostate cancer drugs

    • Last Update: 2018-04-16
    • Source: Internet
    • Author: User
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    Prostate cancer (PCa) is one of the most common malignant tumors in men, accounting for second of the total cancer incidence rate worldwide In the early clinical stage, androgen deprivation therapy (ADT) is mainly used to treat prostate cancer However, almost all patients will eventually develop into fatal castration resistant prostate cancer (CRPC) Although the second generation of antiandrogen drugs approved by FDA, such as enzalutamide and abiraterone, have certain efficacy in alleviating disease progression, patients will soon develop clinical drug resistance Therefore, there is an urgent need for a new strategy to treat drug-resistant prostate cancer In recent years, it is a potential new strategy for the treatment of prostate cancer and drug-resistant prostate cancer to inhibit the epigenetic target bet bromine domain and then affect the androgen receptor signaling pathway Recently, Xu Yong, research group of Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences, has made important progress in the research of new prostate cancer drugs based on bet bromine domain (DOI: 10.1021/acs.jmedchem.8b00103) Frontier research achievements: the development of novel benzo [D] isoxazole type bet bromine domain inhibitors for prostate cancer drug development bromine domain is an epigenetic regulatory factor, which plays a key role in transcriptional activation through the recognition of acetyl lysine on histone, and is related to the occurrence and development of various cancers The bet family belongs to the second family of bromine domain family, including BRD2, BRD3, Brd4 and BRDT In 2014, Nature magazine reported the research work of arul chinnaiyan and Shaoming Wang of the University of Michigan They proposed that the bet bromine domain can interact with AR receptor directly, and affect the expression of AR downstream gene Therefore, targeting the bet bromine domain represents a new strategy for the treatment of prostate cancer Although many bet inhibitors have been developed in recent years, there are still limited compounds that can be used in clinical trials and prostate cancer related functional studies Therefore, in order to enhance our understanding of the therapeutic potential of bet inhibitors, it is still urgent to develop novel and drug-resistant bet domain inhibitors, both in the field of basic research and in clinical practice Xuyong research group established a complete platform for screening and functional evaluation of bromine domain inhibitors Based on this platform, two kinds of bet bromine domain inhibitors, J Med Chem., 2016, 59, 1565 – 1579 and ACS Med Chem Lett., 2018, 9262 – 267, have been developed by making full use of multi-disciplinary cross fusion strategies, such as computer-aided drug design, pharmaceutical chemistry and structural biology Recently, the research group has developed a new benzo [D] isoxazole type bet bromine domain inhibitor, which shows good antitumor activity in vitro and in vivo for prostate cancer Figure 1 Design idea of new bet inhibitors (source: J Med Chem 2018, DOI: 10.1021/acs.jmedchem.8b00103) Based on rational drug design, a new kind of benzo [D] isoxazole skeleton structure simulating acetyl lysine was designed by heterozygous strategy Based on this framework, two kinds of sulfonamides and benzimidazoles were obtained by molecular docking and crystal structure information to guide the optimization of inhibitors The Kd values of the two representative compounds 6I (y06036) and 7m (y06137) with Brd4 (1) were 82 and 81 nm, respectively Compound 6I and 7m showed superior selectivity in the evaluation of 32 representative bromine domain proteins Figure 2 The representative compounds showed good activity and selectivity (source: J Med Chem 2018, DOI: 10.1021/acs.jmedchem.8b00103) In vitro, compounds 6I and 7m can inhibit the proliferation and clonal formation of a variety of prostate cancer cells, and effectively inhibit the expression of AR, AR regulated downstream genes, ERG and myc oncogenes in prostate cancer cells Compound 6I and 7m also showed good tumor growth inhibition effect in c4-2b xenografted mouse prostate cancer model In this study, 6I and 7m obtained by rational drug design strategy provide a new promising lead compound for prostate cancer drug development Fig 3 Compounds show good inhibition effect on AR signaling pathway and tumor growth (source: J Med Chem 2018, DOI: 10.1021/acs.jmedchem.8b00103) This achievement was recently published in Journal of medical chemistry of American Chemical Society The first author of this paper is Zhang Maofeng and Zhang Yan, doctoral students of Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences And research assistant Song Ming, corresponding author is researcher Xu Yong The research work has been strongly supported by Jinan University, University of California Davis, Jilin University, Shanghai Jiaotong University and other collaborators, as well as supported by the national key R & D plan of the Ministry of science and technology, the National Natural Science Foundation, the leading science and technology project of "personalized medicine" of the Chinese Academy of Sciences, the United States prostate cancer fund and other funds Brief introduction of researcher Xu Yong, researcher and doctoral supervisor of Guangzhou Institute of biomedicine and health, Chinese Academy of Sciences, and deputy director of Guangdong Key Laboratory of Biomedical Computing From 2001 to 2004, he studied for a Ph.D in Shanghai Institute of pharmaceutical research, Chinese Academy of Sciences, under the guidance of researcher Chen Kaixian and researcher Jiang Hualiang, engaged in drug discovery and design research From 2004 to 2006, he entered the State Key Laboratory of life and organic, Shanghai Institute of organic Sciences, Chinese Academy of Sciences, and engaged in postdoctoral research From 2006 to 2011, he joined the vanandel Institute in the United States to engage in postdoctoral work and carry out research related to structural biology and drug discovery In 2011, he returned to China to work, and in 2012, he was supported by the "hundred talents plan" of the Chinese Academy of Sciences More than 60 papers have been published in international journals such as nature, science, NAT Med., NAT Structure Mol Biol., cellres., J Med Chem., etc., and the research work has been reviewed by nature, NAT Rev Urol., NAT Genet., etc for many times Won the 2016 Challenge Award of the International Prostate Cancer Foundation (2016 Movember PCF Challenge Award) At present, the research group mainly focuses on the clinical drug resistance needs of tumor and other diseases, and carries out the discovery and confirmation of new drug targets related to nuclear receptor and epigenetic targets, the development of innovative drugs and the study of drug mechanism Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeango app, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.
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