@article{fcaba21ff18546b4a46363f9dbe814d4,
title = "Discovery of Novel Dual-Target Inhibitor of Bromodomain-Containing Protein 4/Casein Kinase 2 Inducing Apoptosis and Autophagy-Associated Cell Death for Triple-Negative Breast Cancer Therapy",
abstract = "Bromodomain-containing protein 4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) is a potential strategy to overcome drug resistance in cancer therapy. The present study describes the synthesis of multiple BRD4–CK2 dual inhibitors based on rational drug design, structure–activity relationship, and in vitro and in vivo evaluations, and 44e was identified to possess potent and balanced activities against BRD4 (IC50 = 180 nM) and CK2 (IC50 = 230 nM). In vitro experiments show that 44e could inhibit the proliferation and induce apoptosis and autophagy-associated cell death of MDA-MB-231 and MDA-MB-468 cells. In two in vivo xenograft mouse models, 44e displays potent anticancer activity without obvious toxicities. Taken together, we successfully synthesized the first highly effective BRD4–CK2 dual inhibitor, which is expected to be an attractive therapeutic strategy for triple-negative breast cancer (TNBC).",
author = "Jifa Zhang and Pan Tang and Ling Zou and Jin Zhang and Juncheng Chen and Chengcan Yang and Gu He and Bo Liu and Jie Liu and Chiang, {Cheng Ming} and Guan Wang and Tinghong Ye and Liang Ouyang",
note = "Funding Information: This work was supported by the National Natural Science Foundation of China (Grant Numbers 81922064, 81874290, 81903502, and 81803365), the Applied Basic Research Programs of Science and Technology Department of Sichuan Province (Grant Numbers 2020YJ0105, 2020YJ0094), the Fundamental Research Funds for the Central Universities (Grant Number 2021SCU12102), China Postdoctoral Science Foundation (Grant Number 2020M673268), and Health Commission of Sichuan Province (Grant Number 20PJ002). C.-M.C.{\textquoteright}s research is sponsored by the U.S. National Institutes of Health (Grant 1RO1CA251698-01)and the Cancer Prevention and Research Institute of Texas (CPRIT; Grants RP180349 and RP190077). Publisher Copyright: {\textcopyright} 2021 American Chemical Society",
year = "2021",
month = dec,
day = "23",
doi = "10.1021/acs.jmedchem.1c01382",
language = "English (US)",
volume = "64",
pages = "18025--18053",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "24",
}