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

• Published in: Journal of medicinal chemistry 2024-07, Vol.67 (14), p.12068-12084
• Main Authors: Jiang, Maojun, Zhang, Hong, Song, Yang, Yin, Fangkui, Hu, Zhiyuan, Li, Xin, Wang, Yuying, Wang, Zheming, Li, Yitong, Wang, Zihan, Zhang, Yanxin, Wang, Siyao, Lu, Shaohua, Xu, Guanghong, Song, Ting, Wang, Ziqian, Zhang, Zhichao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Bcl-2-Like Protein 11 - metabolism; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cell Line, Tumor; Drug Discovery; HSP70 Heat-Shock Proteins - antagonists & inhibitors; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - metabolism; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Molecular Docking Simulation; Protein Binding; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00780

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 (K d = 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.