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

Jifa Zhang, Pan Tang, Ling Zou, Jin Zhang, Juncheng Chen, Chengcan Yang, Gu He, Bo Liu, Jie Liu, Cheng Ming Chiang, Guan Wang, Tinghong Ye, Liang Ouyang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)18025-18053
Number of pages29
JournalJournal of Medicinal Chemistry
Volume64
Issue number24
DOIs
StatePublished - Dec 23 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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