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Chemical Research in Chinese Universities

, Volume 34, Issue 1, pp 67–74 | Cite as

Design and synthesis of novel bispecific molecules for inducing BRD4 protein degradation

  • Shihui Wang
  • Yuming Song
  • Yue Wang
  • Yang Gao
  • Shanshan Yu
  • Qianqian Zhao
  • Xiangqun JinEmail author
  • Haibin LuEmail author
Article

Abstract

Proteolysis targeting chimeras(PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4(BRD4) degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of (9.4±0.6) nmol/L. Furthermore, compound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of (27.6±1.6) nmol/L and capable of inducing degradation of BRD4 protein at 0.5―1.0 μmol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader.

Keywords

Proteolysis targeting chimera(PROTAC) Bromodomain-containing protein 4(BRD4) degrader Bromodomain-containing protein 4(BRD4) inhibitor 

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References

  1. [1]
    Shi J., Vakoc C. R., Molecular cell, 2014, 54(5), 728CrossRefGoogle Scholar
  2. [2]
    Belkina A. C., Denis G. V., Nature Reviews Cancer, 2012, 12(7), 465CrossRefGoogle Scholar
  3. [3]
    Dawson M. A., Kouzarides T., Huntly B. J. P., N. Engl. J. Med., 2012, 367(7), 647CrossRefGoogle Scholar
  4. [4]
    Arrowsmith C. H., Bountra C., Fish P. V., Lee K., Schapira M., Nat. Rev. Drug Discovery, 2012, 11(5), 384CrossRefGoogle Scholar
  5. [5]
    Chung C. W., Prog. Med. Chem., 2012, 51, 1CrossRefGoogle Scholar
  6. [6]
    Filippakopoulos P., Qi J., Picaud S., Shen Y., Smith W. B., Fedorov O., Morse E. M., Keates T., Hickman T. T., Felletar I., Philpott M., Munro S., McKeown M. R., Wang Y., Christie A. L., West N., Ca-meron M. J., Schwartz B., Heightman T. D., La Thangue N., French C. A., Wiest O., Kung A. L., Knapp S., Bradner J. E., Nature, 2010, 468(7327), 1067CrossRefGoogle Scholar
  7. [7]
    Boi M., Gaudio E., Bonetti P., Kwee I., Bernasconi E., Tarantelli C., Rinaldi A., Testoni M., Cascione L., Ponzoni M., Mensah A. A., Sta-this A., Stussi G., Riveiro M. E., Herait P., Inghirami G., Cvitkovic E., Zucca E., Bertoni F., Clin. Cancer Res., 2015, 21(7), 1628CrossRefGoogle Scholar
  8. [8]
    Sakamoto K. M., Kim K. B., Kumagai A., Mercurio F., Crews C. M., Deshaies R. J., Proc. Natl. Acad. Sci. USA, 2001, 98(15), 8554CrossRefGoogle Scholar
  9. [9]
    Toure M., Crews C. M., Angew. Chem. Int. Ed., 2016, 55(6), 1966CrossRefGoogle Scholar
  10. [10]
    Bondeson D. P., Mares A., Smith I. E. D., 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., FaelthSavitski M., Bantscheff M., Cox C., Gordon D. A., Willard R. R., Flanagan J. J., Casillas 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. Biol., 2015, 11(8), 611CrossRefGoogle Scholar
  11. [11]
    Winter G. E., Buckley D. L., Paulk J., Roberts J. M., Souza A., Dhe-Paganon S., Bradner J. E., Science, 2015, 348(6241), 1376CrossRefGoogle Scholar
  12. [12]
    Lu J., Qian Y., Altieri M., Dong H., Wang J., Raina K., Hines J., Winkler J. D., Crew A. P., Coleman K., Crews C. M., Chem. Biol., 2015, 22(6), 755CrossRefGoogle Scholar
  13. [13]
    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), 764CrossRefGoogle Scholar
  14. [14]
    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), 3833CrossRefGoogle Scholar
  15. [15]
    Lohbeck J., Miller A. K., Bioorg. Med. Chem. Lett., 2016, 26(21), 5260CrossRefGoogle Scholar

Copyright information

© Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shihui Wang
    • 1
  • Yuming Song
    • 2
  • Yue Wang
    • 1
  • Yang Gao
    • 1
  • Shanshan Yu
    • 1
  • Qianqian Zhao
    • 1
  • Xiangqun Jin
    • 1
    Email author
  • Haibin Lu
    • 1
    Email author
  1. 1.College of PharmacyJilin UniversityChangchunP. R. China
  2. 2.China-Japan Union Hospital of Jilin UniversityChangchunP. R. China

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