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

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).