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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Raina K., Crews C. M., Curr. Opin. Chem. Biol., 2017, 39, 46
Lai A. C., Crews C. M., Nat. Rev. Drug Discovery, 2017, 16(2), 101
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
Schneekloth A. R., Pucheault M., Tae H. S., Crews C. M., Bioorg. Med. Chem. Lett., 2008, 18(22), 5904
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
Winter G. E., Buckley D. L., Paulk J., Roberts J. M., Souza A., Dhe-Paganon S., Bradner J. E., Science, 2015, 348(6241), 1376
Lai A. C., Toure M., Hellerschmied D., Salami J., Jaime F. S., Ko E., Hines J., Angew. Chem., Int. Ed, 2016, 55(2), 807
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
Zengerle M., Chan K. H., Ciulli A., ACS Chem. Biol., 2015, 10(8), 1770
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
Dawson M. A., Kouzarides T., Huntly B. J. P., N. Engl. J. Med., 2012, 367(7), 647
Arrowsmith C. H., Bountra C., Fish P. V., Lee K., Schapira M., Nat. Rev. Drug Discovery, 2012, 11(5), 384
Chung, C. W., Prog. Med. Chem., 2012, 51, 1
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
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
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
Budin G., Yang K. S., Reiner T., Weissleder R., Angew. Chem. Int. Ed. Engl., 2011, 50(40), 9378
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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