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

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

  • J Med Chem. 2025 Nov 13;68(21):23078-23102. doi: 10.1021/acs.jmedchem.5c01920.
Shouguo Peng 1 2 3,  Yihui Yang 1 4,  Wan Li 1 4,  Songwen Lin 1 2 3,  Shiji Chu 1 2 3,  Tianning Xiong 1 2 3,  Junpu Ge 1 5,  Li Sheng 1 5,  Jinhua Wang 1 4,  Heng Xu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
  • 5 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 41114684 DOI: 10.1021/acs.jmedchem.5c01920
Abstract

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.

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