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Y06014 is a selective BET inhibitor for the treatment of prostate cancer

Abstract

Bromodomain and extra-terminal proteins (BETs) are potential targets for the therapeutic treatment of prostate cancer (PC). Herein, we report the design, the synthesis, and a structure−activity relationship study of 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2(1H)-one derivative as novel selective BET inhibitors. One representative compound, 19 (Y06014), bound to BRD4(1) in the low micromolar range and demonstrated high selectivity for BRD4(1) over other non-BET bromodomain-containing proteins. This molecule also potently inhibited cell growth, colony formation, and mRNA expression of AR-regulated genes in PC cell lines. Y06014 also shows stronger activity than the second-generation antiandrogen enzalutamide. Y06014 may serve as a new small molecule probe for further validation of BET as a molecular target for PC drug development.

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Fig. 1
Fig. 2: Binding mode analysis of 6, 14, and 19 in complex with the BRD4(1) protein.
Scheme 1
Fig. 3: Cocrystal structure of compound 28 with BRD4(1) (PDB ID: 7DHS).
Fig. 4: Thermal shift analysis for compounds 1 and 19 against 8 bromodomain-containing proteins.
Fig. 5
Fig. 6: Compound 19 inhibits prostate cancer cell growth and AR-regulated gene expression.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  2. 2.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  3. 3.

    Huggins C, Stevens RE, Hodges CV. Studies on prostate cancer II the effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209–23.

    CAS  Article  Google Scholar 

  4. 4.

    Balk SP. Androgen receptor as a target in androgen-independent prostate cancer. Urology. 2002;60:132–8.

    Article  Google Scholar 

  5. 5.

    Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  Google Scholar 

  6. 6.

    Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–61.

    CAS  Article  Google Scholar 

  7. 7.

    Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao YH, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    CAS  Article  Google Scholar 

  8. 8.

    Asangani IA, Dommeti VL, Wang XJ, Malik R, Cieslik M, Yang RD, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.

    CAS  Article  Google Scholar 

  9. 9.

    De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  Google Scholar 

  10. 10.

    Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    CAS  Article  Google Scholar 

  11. 11.

    Fizazi K, Albiges L, Loriot Y, Massard C. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticanc. 2015;15:1007–17.

    CAS  Article  Google Scholar 

  12. 12.

    Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.

    CAS  Article  Google Scholar 

  13. 13.

    Sanchez R, Meslamani J, Zhou MM. The bromodomain: from epigenome reader to druggable target. Biochim Biophys Acta. 2014;1839:676–85.

    CAS  Article  Google Scholar 

  14. 14.

    Sahai V, Redig AJ, Collier KA, Eckerdt FD, Munshi HG. Targeting BET bromodomain proteins in solid tumors. Oncotarget. 2016;7:53997–4009.

    Article  Google Scholar 

  15. 15.

    Welti J, Sharp A, Yuan W, Dolling D, Rodrigues DN, Figueiredo I, et al. Targeting bromodomain and extra-terminal (BET) family proteins in castration-resistant prostate cancer (CRPC). Clin Cancer Res. 2018;24:3149–62.

    CAS  Article  Google Scholar 

  16. 16.

    Xiang QP, Zhang Y, Li JG, Xue XQ, Wang C, Song M, et al. Y08060: a selective BET inhibitor for treatment of prostate cancer. ACS Med Chem Lett. 2018;9:262–7.

    CAS  Article  Google Scholar 

  17. 17.

    Xue XQ, Zhang Y, Wang C, Zhang MF, Xiang QP, Wang JJ, et al. Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer. Eur J Med Chem. 2018;152:542–59.

    CAS  Article  Google Scholar 

  18. 18.

    Zhang M, Zhang Y, Song M, Xue X, Wang J, Wang C, et al. Structure-based discovery and optimization of benzo[d]isoxazole derivatives as potent and selective BET inhibitors for potential treatment of castration-resistant prostate cancer (CRPC). J Med Chem. 2018;61:3037–58.

    CAS  Article  Google Scholar 

  19. 19.

    Zhang GT, Plotnikov AN, Rusinova E, Shen T, Morohashi K, Joshua J, et al. Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J Med Chem. 2013;56:9251–64.

    CAS  Article  Google Scholar 

  20. 20.

    Zhao LL, Cao DY, Chen TT, Wang YQ, Miao ZH, Xu YC, et al. Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain. J Med Chem. 2013;56:3833–51.

    CAS  Article  Google Scholar 

  21. 21.

    Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, et al. Discovery of 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as highly potent and selective bromodomain and extra-terminal (BET) bromodomain inhibitors. J Med Chem. 2020;63:3956–75.

    CAS  Article  Google Scholar 

  22. 22.

    Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.

    CAS  Article  Google Scholar 

  23. 23.

    Seal J, Lamotte Y, Donche F, Bouillot A, Mirguet O, Gellibert F, et al. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem Lett. 2012;22:2968–72.

    CAS  Article  Google Scholar 

  24. 24.

    Mirguet O, Gosmini R, Toum J, Clement CA, Barnathan M, Brusq JM, et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem. 2013;56:7501–15.

    CAS  Article  Google Scholar 

  25. 25.

    Bui MH, Lin XY, Albert DH, Li LM, Lam LT, Faivre EJ, et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 2017;77:2976–89.

    CAS  Article  Google Scholar 

  26. 26.

    McDaniel KF, Wang L, Soltwedel T, Fidanze SD, Hasvold LA, Liu DC, et al. Discovery of N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/mivebresib), a potent and orally available bromodomain and extraterminal domain (BET) family bromodomain inhibitor. J Med Chem. 2017;60:8369–84.

    CAS  Article  Google Scholar 

  27. 27.

    Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, et al. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J Med Chem. 2013;56:3217–27.

    CAS  Article  Google Scholar 

  28. 28.

    Xue X, Zhang Y, Liu Z, Song M, Xing Y, Xiang Q, et al. Discovery of benzo[cd]indol-2(1H)-ones as potent and specific BET bromodomain inhibitors: structure-based virtual screening, optimization, and biological evaluation. J Med Chem. 2016;59:1565–79.

    CAS  Article  Google Scholar 

  29. 29.

    A study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK525762 in subjects with NUT midline carcinoma (NMC) and other cancers. Clinical Trials Apr 30 2012: https://clinicaltrials.gov/ct2/show/NCT01587703 (2012). Accessed 11 Mar 2018.

  30. 30.

    A study of ZEN003694 in patients with metastatic castration-resistant prostate cancer. Clinical Trials Mar 10, 2016: https://clinicaltrials.gov/ct2/show/NCT02705469 (2016). Accessed 11 Mar 2018.

  31. 31.

    Safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-5829 as a single agent and in combination with enzalutamide in participants with metastatic castrate-resistant prostate cancer. Clinical Trials Nov 17, 2015: https://clinicaltrials.gov/ct2/show/NCT02607228 (2015). Accessed 11 Mar 2018.

  32. 32.

    A dose-finding study of OTX105/MK-8628, a small molecule inhibitor of the bromodomain and extra-terminal (BET) proteins, in adults with selected advanced solid tumors (MK-8628-003). Clinical Trials Oct 8, 2014: https://clinicaltrials.gov/ct2/show/NCT02259114 (2014). Accessed 11 Mar 2018.

  33. 33.

    Xiang QP, Wang C, Zhang Y, Xue XQ, Song M, Zhang C, et al. Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer. Eur J Med Chem. 2018;147:238–52.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge financial support from the Chinese National Programs for Key Research and Development (grant 2019YFE0123700, 2016YFB0201701), the Key International Cooperation Projects of the Chinese Academy of Sciences (grant 154144KYSB20180044 and 154144KYSB20180063), the Chinese Academy of Sciences STS Program (grant KFJ-STS-QYZX-090), the National Natural Science Foundation of China (grant 81673357), the Natural Science Foundation of Guangdong province (grant 2015A030312014, 2019A1515110592), the State Key Laboratory of Respiratory Disease (grant SKLRD-Z-202018), Guangdong Provincial Key Laboratory of Biocomputing (grant 2016B030301007), Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory, grant 2018GZR110105016), the Natural Science Foundation of Jiangsu Province (grant BK20190246) and the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (grant 19KJB350011). The authors also gratefully acknowledge support from the Guangzhou Branch of the Supercomputing Center of the Chinese Academy of Sciences.

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YX and LJX designed the research. TBW, QPX, CW, CW, CZ, MFZ, and ZXL conduct the research; TBW, QPX, YZ, LJX, and YX analyzed the date and wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yan Zhang or Lin-jiu Xiao or Yong Xu.

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The authors declare no competing interests.

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Wu, Tb., Xiang, Qp., Wang, C. et al. Y06014 is a selective BET inhibitor for the treatment of prostate cancer. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00614-7

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Keywords

  • prostate cancer
  • bromodomain inhibitor
  • BRD4
  • Y06014
  • androgen receptor

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