2. Academic Validation
  3. 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

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

  • J Med Chem. 2021 Dec 23;64(24):18025-18053. doi: 10.1021/acs.jmedchem.1c01382.
Jifa Zhang 1,  Pan Tang 1,  Ling Zou 1,  Jin Zhang 1 2,  Juncheng Chen 1,  Chengcan Yang 1,  Gu He 1,  Bo Liu 1,  Jie Liu 1,  Cheng-Ming Chiang 3,  Guan Wang 1,  Tinghong Ye 1,  Liang Ouyang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041 Sichuan, China.
  • 2 School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
  • 3 Simmons Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
PMID: 34908415 DOI: 10.1021/acs.jmedchem.1c01382
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).

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