Discovery of Novel PI3K/BRD4 Dual Inhibitors for Esophageal Cancer: Rational Design, Optimization, and Senescence-Inducing Mechanisms.

The discovery of novel targeted therapies for esophageal cancer represents an urgent clinical need. Herein, we reported the rational design and synthesis of novel PI3K/BRD4 dual inhibitors for the treatment of esophageal cancer. Systematic structure-activity relationship studies identified compound 23 as a potent dual-targeting inhibitor that effectively suppresses PI3K and BRD4 signaling. In vitro, 23 inhibited proliferation, migration, invasion, and colony formation of esophageal cancer cells. In vivo, 23 demonstrated anticancer efficacy comparable to that of the BKM120/JQ1 combination treatment in a KYSE450 xenograft mouse model. Mechanistically, 23 induces cellular senescence via the AMPK-p27 pathway. Significantly, the senolytic agent ABT737 enhanced the efficacy of compound 23 through the selective clearance of senescent cancer cells. Collectively, this work establishes 23 as a promising PI3K/BRD4 dual-targeting lead and supports senescence induction combined with senolytics as a novel strategy for esophageal cancer treatment.