2. Academic Validation
  3. Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer

Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer

  • J Med Chem. 2026 Feb 26;69(4):4512-4547. doi: 10.1021/acs.jmedchem.5c03168.
Yi-Zhe Zhang 1,  Hui-Juan Zhu 1,  Xiao-Xiao Zhou 1,  Shi-Jie Li 1,  Di Han 2,  Feng-Xiang Liu 2,  Hui-Min Zhou 1,  Xin-Yu Jiang 1,  Yuan-Yuan Guan 1,  Hui-Ru Ren 1,  Ying Wang 1,  Wen-Jing Dai 1,  Yi-Bo Ban 1,  Nan Su 3,  Yong-Cheng Ma 4,  Yong-Tao Xu 2,  Sai-Qi Wang 5 6,  Ying-Chao Duan 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan Province 453003, PR China.
  • 2 School of Medical Engineering, Xinxiang Key Laboratory of Biomedical Information Research, Henan International Joint Laboratory of Neural Information analysis and Drug Intelligent Design, Xinxiang Medical University, Xinxiang, Henan Province 453003, PR China.
  • 3 College of Food and Biological Engineering, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan Province 450046, PR China.
  • 4 Zhengzhou University Central China Fuwai Hospital, Henan Key Laboratory of Individualized Drug Therapy for Cardiovascular Diseases, Zhengzhou, Henan Province 451464, PR China.
  • 5 Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Province Engineering Research Center for of Intractable Digestive Tract Tumor Precision Therapy & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, Henan Province 450008, PR China.
  • 6 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Zhengzhou, Henan Province 450052, PR China.
PMID: 41650352 DOI: 10.1021/acs.jmedchem.5c03168
Abstract

CBP/p300 and BRD4 synergistically drive prostate Cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values ranging from 8.8 pM to 10.5 nM in PC-3 prostate Cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple Cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every Other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate Cancer and warrants further development.

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