Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy

  • J Med Chem. 2024 Jul 25;67(14):12068-12084. doi: 10.1021/acs.jmedchem.4c00780.
Maojun Jiang  1 ,  Hong Zhang  1 ,  Yang Song  2 ,  Fangkui Yin  1 ,  Zhiyuan Hu  3 ,  Xin Li  1 ,  Yuying Wang  3 ,  Zheming Wang  1 ,  Yitong Li  1 ,  Zihan Wang  1 ,  Yanxin Zhang  3 ,  Siyao Wang  1 ,  Shaohua Lu  1 ,  Guanghong Xu  1 ,  Ting Song  1 ,  Ziqian Wang  1 ,  Zhichao Zhang  1
Affiliations
  • 1. Cancer Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 2. Department of Hematology, Central Hospital of Dalian University of Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 3. School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
PMID: 39012838 DOI: 10.1021/acs.jmedchem.4c00780
Abstract

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 μg/mL) compared to S1g-10. It maintains comparable Apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.

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