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Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein–Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-16 , 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
Affiliation  

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.

中文翻译:


通过支架跳跃策略发现联苯衍生物靶向慢性粒细胞白血病中的 Hsp70-Bim 蛋白-蛋白相互作用



Hsp70-Bim 蛋白-蛋白相互作用 (PPI) 是慢性粒细胞白血病 (CML) 治疗中最新确定的特定靶点。在此,我们通过S1g-10的支架跳跃开发了一类新的 Hsp70-Bim PPI 抑制剂,S1g-10 是迄今为止最有效的 Hsp70-Bim PPI 抑制剂。通过构效关系(SAR)研究,我们获得了联苯支架化合物JL-15 ,其 Hsp70-Bim PPI 抑制提高了 5.6 倍( K d = 123 vs 688 nM),水溶性提高了 4 倍( 29.42 vs 7.19 μg/mL) 与S1g-10相比。它以 Hsp70-Bim 依赖性方式对 TKI 敏感和 TKI 耐药 CML 细胞系保持与S1g-10相当的细胞凋亡诱导能力。此外,通过SAR、 1 H- 15 N TRSOY-NMR和分子对接,我们发现Lys319是Hsp70-Bim PPI界面中的“热点”。总的来说,这些结果为 Hsp70-Bim PPI 抑制剂的合理设计提供了一种新颖的化学支架和结构见解。
更新日期:2024-07-16
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