Discovery of novel BCL6-Targeting PROTACs with effective antitumor activities against DLBCL in vitro and in vivo

  • Eur J Med Chem. 2024 Nov 5:277:116789. doi: 10.1016/j.ejmech.2024.116789.
Dazhao Mi  1 ,  Cheng Li  2 ,  Yuzhan Li  1 ,  Mingyue Yao  3 ,  Yan Li  4 ,  Keyu Hong  5 ,  Chengying Xie  6 ,  Yihua Chen  7
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3. Lingang Laboratory, Shanghai, 200031, China.
  • 4. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 5. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 6. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China. Electronic address: [email protected].
  • 7. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China; School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunna, 650500, China; Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, Yunnan, 650500, China. Electronic address: [email protected].
PMID: 39208743 DOI: 10.1016/j.ejmech.2024.116789
Abstract

The transcriptional repressor B cell lymphoma 6 (BCL6) plays a critical role in driving tumorigenesis of diffuse large B-cell lymphoma (DLBCL). However, the therapeutic potential of inhibiting or degrading BCL6 for DLBCL has not been thoroughly understood. Herein, we reported the discovery of a series of novel BCL6-targeting PROTACs based on our previously reported N-phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound DZ-837 degraded BCL6 with DC50 values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that DZ-837 induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, DZ-837 significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of DZ-837 with Btk Inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that DZ-837 is an effective BCL6 Degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib.

Keywords
BCL6; DLBCL; Lead compound; PROTACs; Pyrimidinamine scaffold.
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