The Xu Yong collaborative team of Guangzhou Health Institute has made new progress in the study of anti-prostate cancer drugs based on the new target ROR

Prostate cancer (PCa) is a common malignancy in men. Among the new cancers in men worldwide in 2020, prostate cancer is the second most frequent malignancy. Prostate cancer accounts for 6.8% of all male cancer deaths worldwide, and its fatality rate ranks fifth among male cancers. These data suggest that prostate cancer has seriously affected men's physical health. Prostate cancer is a hormone-dependent disease in which excessive activation of androgen receptors (AR) drives the development of prostate cancer and the growth of tumors. Most of the drugs currently used to treat prostate cancer are targeting androgen receptors (AR), such as the more popular drugs enzalutamide and Apalutamide on the market. But these drugs eventually inevitably develop clinical resistance. Important mechanisms of drug resistance include AMPL, mutation and shear (AR-V7) expression. Finding new targets and new mechanisms to overcome abnormal AR signals and then solve the problem of prostate cancer drug resistance has always been a hot spot and difficulty in domestic and foreign research.

Recently, xu Yong's research group of Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, is in the international journal of medicinal chemistry J. Med. Chem. published a paper titled "Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally available RORγ Inverse Agonist" The paper designed and synthesized a novel small molecule inhibitor for RORγ, a new target for prostate cancer treatment, and finally obtained a drug candidate XY123 that can be used for clinically resistant treatment of prostate cancer.

Retinoic acid receptor-related orphan receptor γ γ (RORγ) is a ligand-dependent transcription factor that plays a key role in life processes such as growth and development, immunity, and metabolism by regulating the expression of related genes. Xu Yong's team has been conducting research on the function of the nuclear receptor RORγ and small molecule inhibitors for a long time, and has made a series of important progress, developing a variety 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）。 In addition, the research group confirmed for the first time in previous studies (Nature Medicine, 2016, 22, 488-496) that the nuclear receptor RORγ is a new target for prostate cancer and its drug-resistant therapy. It has been found that the nuclear receptor RORγ plays an important role in AR expression, transcription, activation and other processes as a key driver. Targeted RORγ can effectively affect AR expression and its downstream signaling pathways, providing a new therapeutic strategy for the treatment of clinical resistance to prostate cancer.

Recently, the team obtained a series of benzimidazole RORγ small molecule inhibitors through virtual screening, structure-based drug design and structure-activity studies, which exhibit significant inhibitory activity against RORγ. Representative compound XY123 effectively inhibits the transcriptional activity of RORγ (IC50 = 64 nM) and enhances the thermal stability of RORγ-LBD (ΔTm = 10.5 °C). At the same time, XY123 has superior selectivity, good metabolic stability and pharmacokinetic properties (t1/2 = 4.98 h, F = 32%). In addition, XY123 also carried out research on the evaluation of prostate cancer activity and the mechanism of overcoming drug resistance. The results showed that XY123 could inhibit the proliferation and cloning of a variety of prostate cancer cells, and at the same time effectively inhibit the expression of AR-regulated downstream genes in prostate cancer cells. XY123 can also effectively inhibit the expression of AR full-length and AR mutants in prostate cancer cells. In a mouse model of prostate cancer transplanted with 22Rv1 xenograft, long-term complete regression of tumors can be achieved by oral administration of XY123. XY123 can be used as a promising lead compound in the development of prostate cancer and its clinically resistant drugs.

The first author of the paper is Wu Xishan, a postdoctoral fellow of Xu Yong's research group, Shen Hui, a doctoral student, and Zhang Yan, a postdoctoral fellow, and Xu Yong is the corresponding author. The research has been supported by the National Key Research and Development Program, the Key Project of International Cooperation of the Chinese Academy of Sciences, the STS Project of the Chinese Academy of Sciences and the "Major New Drug Creation" of the National Science and Technology Major Project.

The Xu Yong collaborative team of Guangzhou Health Institute has made new progress in the study of anti-prostate cancer drugs based on the new target RORγ