2. Academic Validation
  3. Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy

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

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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