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Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

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Fig. 1: Structures of representative RORγ inverse agonists.
Fig. 2: 3D presentation of binding modes of ligands with RORγ LBD (PDB code: 4QM0).
Scheme 1
Fig. 3: Cocrystal structure of compound 13e in complex with the RORγ LDB (PDB code: 7XQE).
Fig. 4: Predicted binding mode of compound 14a (yellow) in complex with RORγ LBD (PDB code: 4QM0).
Fig. 5: Compound 13e suppressed colony formation and expression of AR, AR-regulated gene and protein.
Fig. 6: Compounds 13e and 14a inhibited the migration of 22Rv1 cells.
Fig. 7: Compounds 13e and 14a induced apoptosis in 22Rv1 cells.
Fig. 8: In vivo effect of compounds 13e and 14a on tumor volume, tumor weight, and body weight in xenograft model of 22Rv1.

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Acknowledgements

This work was supported in part by grants from the National Key R&D Program of China (grant 2019YFE0123700 and 2022YFE0210600), the National Natural Science Foundation of China (grant 82173745), the Chinese Academy of Sciences STS Program (grant KFJ-STS-QYZX-090), the Guangdong Basic and Applied Basic Research Foundation (grant 2023A1515010418 and 2020A1515110793), the Science and Technology Program of Guangzhou, China (grant 2024A04J4313 and 202201010138), the China Postdoctoral Science Foundation, the Guangdong Provincial Grant for Belt and Road Joint Laboratory (grant 2022A0505090006), the Guangdong Provincial Postdoctoral Special Funding. We thank the staff from the BL19U1 beamline of the National Facility for Protein Science Shanghai (NFPS) at Shanghai Synchrotron Radiation Facility for assistance during data collection. The authors gratefully acknowledge the support from the Guangzhou Branch of the Supercomputing Center of Chinese Academy of Sciences and the Scientific Data Center of Guangzhou Institutes of Biomedicine and Health, CAS (No. 011). The authors gratefully thank Drs Sabine Puch and Carolin Lange (German Aerospace Center, Project Management Agency (DLR-PT)) for their efforts in establishing the collaboration and suggestion, guidance and useful discussions during the project within the EU funded Sino-EU PerMed Project.

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  1. These authors contributed equally: Xi-shan Wu, Xiao-yu Luo

Authors and Affiliations

  1. State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou, 510530 China; Guangzhou Medical University, Guangzhou, 511436, China

    Xi-shan Wu, Xiao-yu Luo, Cheng-chang Li, Cheng Zhang, Xiao-shan Chen, Zhi-fang Lu, Tong Wu, Hao-nan Yu, Qing-qing Hu, Hui Shen, Yong Xu & Yan Zhang

  2. University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China

    Xiao-yu Luo & Xiao-shan Chen

  3. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Xiao-fan Zhao

  4. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Zhi-fang Lu, Tong Wu & Yong Xu

  5. Jiangsu S&T Exchange Center with Foreign Countries, No. 175 Longpan Road, Nanjing, 210042, China

    Chao Peng

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Contributions

YX, XSW, YZ and XYL conceived and designed the research. XSW, XYL, CCL, XFZ, CZ, XSC, ZFL, TW, HHY, CP, QQH, HS conduct the research. XSW wrote the manuscript. YX, XSW, YZ and XYL revised the revised the manuscript. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Xi-shan Wu, Yong Xu or Yan Zhang.

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Wu, Xs., Luo, Xy., Li, Cc. et al. Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01274-z

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