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.

食管癌新型靶向治疗药物的研发是亟待满足的临床需求。在此，我们报道了用以治疗食管癌的新型磷脂酰肌醇3-激酶/溴结构域蛋白4(PI3K/BRD4)双重抑制剂的合理设计与合成。系统性构效关系研究筛选得到化合物23，其为强效双重靶点抑制剂，可有效阻断PI3K与BRD4的信号通路。体外实验结果表明，化合物23可抑制食管癌细胞的增殖、迁移、侵袭及集落形成能力。体内实验方面，在KYSE450异种移植小鼠模型中，化合物23展现出与BKM120与JQ1联合给药方案相当的抗癌活性。机制研究显示，化合物23可通过腺苷酸活化蛋白激酶(AMPK)-p27通路诱导细胞衰老。值得注意的是，衰老清除剂(senolytic agent) ABT737可通过选择性清除衰老癌细胞，增强化合物23的治疗效果。综上，本研究确立了化合物23作为极具潜力的PI3K/BRD4双重靶点先导化合物的地位，并证实诱导衰老联合衰老清除疗法可作为食管癌治疗的全新策略。