2. Academic Validation
  3. Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity

Discovery of highly potent dual GSPT1/BRD4 degraders with anti-AML activity

  • Eur J Med Chem. 2025 Apr 15:288:117381. doi: 10.1016/j.ejmech.2025.117381.
Yue Xu 1,  Hang Yang 1,  Yunxuan Li 2,  Yuying Qi 1,  Fangling Zhao 1,  Yun Hong 1,  Binbin Cheng 3,  Zebei Lu 3,  Jiaming Zhang 2,  Chunyi Guo 2,  Jie Fu 1,  Qinrong Lin 1,  Chunhong Chen 1,  Ningning Shi 1,  Jianping Cai 1,  Ke Li 4,  Shuanghu Wang 5,  Ruijuan Gao 6,  Dapeng Dai 7
Affiliations

Affiliations

  • 1 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital /National Center of Gerontology of National Health Commission, Beijing, 100730, PR China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China.
  • 3 Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, 323020, PR China.
  • 4 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address: like@imb.pumc.edu.cn.
  • 5 Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, 323020, PR China. Electronic address: wangshuanghu@lsu.edu.cn.
  • 6 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China. Electronic address: gaoruijuan@imb.cams.cn.
  • 7 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital /National Center of Gerontology of National Health Commission, Beijing, 100730, PR China. Electronic address: daidapeng3702@bjhmoh.cn.
PMID: 39965406 DOI: 10.1016/j.ejmech.2025.117381
Abstract

Translational readthrough (TR) regulation has emerged as a promising therapeutic strategy for Cancer treatment. Utilizing a constructed monoclonal cell line AG-9, designed for screening compounds that induce TR, we identified a BRD4-targeted PROTAC molecule, dBET57, that promotes TR by degrading GSPT1. Notably, dBET57 exhibited significant antiproliferative activity against acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) cells across a diverse panel of tumor cell lines. Building on these findings, we optimized the structure of dBET57, leading to the development of analogs with enhanced dual-target degradation capabilities. Most of these optimized degraders demonstrated superior antiproliferative activity in vitro against various AML and NHL cell lines when compared to dBET57. Among them, DP-15 emerged as a particularly promising candidate, exhibiting significant Anticancer activity against both AML and NHL cells while maintaining acceptable safety profiles for normal leukocytes. Furthermore, DP-15 demonstrated enhanced antitumor efficacy in mouse cell-derived xenograft (CDX) models. Our findings highlight the potential of dual BRD4 and GSPT1 degraders, such as DP-15, as effective therapeutic agents for the treatment of hematological malignancies.

Keywords

Acute myeloid leukemia (AML); Bromodomain-containing protein 4 (BRD4); G1 to S phase transition protein 1 (GSPT1); Non-hodgkin lymphoma (NHL); PROTAC; Structure activity relationship (SAR).

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