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Research team led by Xu Yong at GIBH has made new progress on anti-prostate cancer drugs targeting on the new target RORγ


Prostate cancer (PCa) is the most common malignancy and the fifth leading cause of death from malignancy in men. AR signaling pathway plays an important role in the occurrence and development of prostate cancer. AR gene amplification, mutation and spliced variant expression make the treatment of prostate cancer face drug resistance problems. How to develop new targets to overcome clinical drug resistance is a key issue that needs to be resolved in this field. 

On June 24, Xu Yong's research group published a research article entitled "Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally available RORγ Inverse Agonist" on J Med Chem This study focuses on the new target RORγ for the treatment of prostate cancer and describes the design, synthesis and biological evaluation of RORγ small molecule inhibitors.  

Xu Yong’s team has conducted long-term research on the biological function of RORγ, and developed various types of RORγ small molecule inhibitors (Eur J Med Chem 2014, 78, 431-441; Acta Pharmacol Sin 2016, 37, 1516-1524; Eur J Med Chem 2016, 116, 13-26; J Med Chem 2019, 62, 4716-4730). Previously, this research team confirmed that RORγ is a key factor driving AR expression and can be used as a new target for the treatment of prostate cancer, providing a new strategy for overcoming the clinical drug resistance. 

Recently, the team obtained a series of benzimidazole derivatives as RORγ inhibitors through virtual screening, structure-based drug design and structure-activity relationship studies. These compounds showed significant inhibitory activity against RORγ. The represent compound XY123 displayed a potent activity with an IC50 value of 64 nM and a thermal shift of 10.5 °C. Meanwhile, XY123 showed excellent selectivity against other nuclear receptors. It demonstrated good metabolic stability and pharmacokinetic property with reasonable oral bioavailability (32.41%) and moderate half-life (t1/2 = 4.98 h). XY123 also potently suppressed cell proliferation, colony formation, and the expression of androgen receptor (AR)-regulated genes in AR-positive prostate cancer cell lines. Significantly, oral administration of XY123 achieved complete and long-lasting tumor regression in the 22Rv1 xenograft tumor model in mice. XY123 may serve as a new valuable lead compound for further development of drugs for the treatment of prostate cancer. 

In this work, Wu Xishan, Shen Hui, and Zhang Yan contributed equally under the guidance of Xu Yong, the corresponding author of this article. This work was supported in part by grants from the National Key R&D Program of China, the Key International Cooperation Projects of the Chinese Academy of Sciences, the Chinese Academy of Sciences STS Program, the National Science & Technology Major ProjectKey New Drug Creation and Manufacturing Program”, and others. 


XU Yong

E-mail: xu_yong@gibh.ac.cn