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Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

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Abstract

In this paper, we synthesized a series of proteolysis targeting chimeras(PROTACs) using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC50 value of (18.6±1.3) nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of (34.2±4.3) nmol/L and capable of inducing de-gradation of BRD4 protein at 0.4—0.6 μmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRD4 degrader.

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References

  1. Raina K., Crews C. M., Curr. Opin. Chem. Biol., 2017, 39, 46

    Article  CAS  Google Scholar 

  2. Lai A. C., Crews C. M., Nat. Rev. Drug Discovery, 2017, 16(2), 101

    Article  CAS  Google Scholar 

  3. Galdeano C., Gadd M. S., Soares P., Scaffidi S., van Molle I., Birced I., Hewitt S., Dias D. M., Ciulli A., J. Med. Chem., 2014, 57(20), 8657

    Article  CAS  Google Scholar 

  4. Schneekloth A. R., Pucheault M., Tae H. S., Crews C. M., Bioorg. Med. Chem. Lett., 2008, 18(22), 5904

    Article  CAS  Google Scholar 

  5. Sakamoto K. M., Kim K. B., Kumagai A., Mercurio F., Crews C. M., Deshaies R. J., Proc. Natl. Acad. Sci. USA, 2001, 98(15), 8554

    Article  CAS  Google Scholar 

  6. Winter G. E., Buckley D. L., Paulk J., Roberts J. M., Souza A., Dhe-Paganon S., Bradner J. E., Science, 2015, 348(6241), 1376

    Article  CAS  Google Scholar 

  7. Lai A. C., Toure M., Hellerschmied D., Salami J., Jaime F. S., Ko E., Hines J., Angew. Chem., Int. Ed, 2016, 55(2), 807

    Article  CAS  Google Scholar 

  8. Okuhira K., Demizu Y., Hattori T., Ohoka N., Shibata N., Nishima-ki-Mogami T., Okuda H., Kurihara M., Naito M., Cancer Sci., 2013, 104(11), 1492

    Article  CAS  Google Scholar 

  9. Zengerle M., Chan K. H., Ciulli A., ACS Chem. Biol., 2015, 10(8), 1770

    Article  CAS  Google Scholar 

  10. Bondeson D. P., Mares A., Smith I. E., Ko E., Campos S., Miah A. H., Mulholland K. E., Routly N., Buckley D. L., Gustafson J. L., Zinn N., Grandi P., Shimamura S., Bergamini G., Faelth-Savitski M., Bant-scheff M., Cox C., Gordon D. A., Willard R. R., Flanagan J. J., Ca-sillas L. N., Votta B. J., den Besten W., Famm K., Kruidenier L., Carter P. S., Harling J. D., Churcher I., Crews C. M., Nat. Chem. Bi-ol., 2015, 11(8), 611

    Article  CAS  Google Scholar 

  11. Dawson M. A., Kouzarides T., Huntly B. J. P., N. Engl. J. Med., 2012, 367(7), 647

    Article  CAS  Google Scholar 

  12. Arrowsmith C. H., Bountra C., Fish P. V., Lee K., Schapira M., Nat. Rev. Drug Discovery, 2012, 11(5), 384

    Article  CAS  Google Scholar 

  13. Chung, C. W., Prog. Med. Chem., 2012, 51, 1

    Article  CAS  Google Scholar 

  14. Raina K., Lu J., Qian Y., Altieri M., Gordon D., Rossi A. M., Wang J., Chen X., Dong H., Siu K., Winkler J. D., Crew A. P., Crews C. M., Coleman K. G., Proc. Natl. Acad. Sci. USA, 2016, 113(26), 7124

    Article  CAS  Google Scholar 

  15. Chen L., Yap J. L., Yoshioka M., Lanning M. E., Fountain R. N., Raje M., Scheenstra J. A., Strovel J. W., Fletcher S., ACS Med. Chem. Lett., 2015, 6(7), 764

    Article  CAS  Google Scholar 

  16. Zhao L., Cao D., Chen T., Wang Y., Miao Z., Xu Y., Chen W., Wang X., Li Y., Du Z., Xiong B., Li J., Xu C., Zhang N., He J., Shen J., J. Med. Chem., 2013, 56(10), 3833

    Article  CAS  Google Scholar 

  17. Budin G., Yang K. S., Reiner T., Weissleder R., Angew. Chem. Int. Ed. Engl., 2011, 50(40), 9378

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. College of Pharmacy, Jilin University, Changchun, 130021, P. R. China

    Shihui Wang, Yue Wang, Yang Gao, Shanshan Yu, Qianqian Zhao, Xiangqun Jin & Haibin Lu

  2. Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130021, P. R. China

    Haiyan Li

Authors
  1. Shihui Wang
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  2. Haiyan Li
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  3. Yue Wang
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  4. Yang Gao
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  5. Shanshan Yu
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  6. Qianqian Zhao
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  7. Xiangqun Jin
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  8. Haibin Lu
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Corresponding authors

Correspondence to Xiangqun Jin or Haibin Lu.

Additional information

Supported by the Science and Technology Development Plan Projects of Jilin Province, China(No.20170311057YY).

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Wang, S., Li, H., Wang, Y. et al. Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation. Chem. Res. Chin. Univ. 34, 221–228 (2018). https://doi.org/10.1007/s40242-018-7299-7

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  • DOI: https://doi.org/10.1007/s40242-018-7299-7

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