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 <b>23</b> as a potent dual-targeting inhibitor that effectively suppresses PI3K and BRD4 signaling. <i>In vitro</i>, <b>23</b> inhibited proliferation, migration, invasion, and colony formation of esophageal cancer cells. <i>In vivo</i>, <b>23</b> demonstrated anticancer efficacy comparable to that of the BKM120/JQ1 combination treatment in a KYSE450 xenograft mouse model. Mechanistically, <b>23</b> induces cellular senescence via the AMPK-p27 pathway. Significantly, the senolytic agent ABT737 enhanced the efficacy of compound <b>23</b> through the selective clearance of senescent cancer cells. Collectively, this work establishes <b>23</b> as a promising PI3K/BRD4 dual-targeting lead and supports senescence induction combined with senolytics as a novel strategy for esophageal cancer treatment.