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Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance


As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 μM) and GR (IC50 = 17.81 μM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

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Fig. 1: SBVS of AR and GR antagonists.
Fig. 2: H18 directly binds to AR and GR.
Fig. 3: Biological evaluation of the compound H18 identified by SBVS.
Fig. 4: MD simulations and key residues in the AR LBD and GR LBD for the binding of H18.
Fig. 5: Biological evaluation of H18 analogs.
Fig. 6: MD simulations and key residues in the AR LBD and GR LBD for the binding of HD57.
Fig. 7: Study on AR mutants.
Fig. 8: Regulation of AR LBD-ligand interactions by T877G and W741C mutations.


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This research was supported by National Key R&D Program of China (2019YFE0111300), National Natural Science Foundation of China (22220102001, 22273049), and Zhejiang Provincial Natural Science Foundation of China (LD22H300001).

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Authors and Affiliations



DL, TJH, and HGX initiated and supervised the research. XC and XH conducted virtual screening, compound validations and biological assays. XYW, HTW, JPP, JNL, LHS, XHX, and LX performed part of in vitro experiments and interpreted part of the data. WFZ performed part of in silico experiments. XC, XPH, TJH, and DL wrote the manuscript, and other authors contributed specific parts of the manuscript. HGX, TJH, and DL assume responsibility for the manuscript in its entirety. All authors have given approval to the final version of the manuscript.

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Correspondence to Hong-guang Xia, Ting-jun Hou or Dan Li.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Chai, X., Hu, Xp., Wang, Xy. et al. Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance. Acta Pharmacol Sin (2023).

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  • prostate cancer
  • androgen receptor
  • glucocorticoid receptor
  • dual antagonists
  • antiandrogen resistance


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