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 <i>in vitro</i> and <i>in vivo</i> evaluations, and <b>44e</b> was identified to possess potent and balanced activities against BRD4 (IC₅₀ = 180 nM) and CK2 (IC₅₀ = 230 nM). <i>In vitro</i> experiments show that <b>44e</b> could inhibit the proliferation and induce apoptosis and autophagy-associated cell death of MDA-MB-231 and MDA-MB-468 cells. In two <i>in vivo</i> xenograft mouse models, <b>44e</b> 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).