Cancer Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, China.
Department of Hematology, Central Hospital of Dalian University of Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
J Med Chem. 2024 Jul 25;67(14):12068-12084. doi: 10.1021/acs.jmedchem.4c00780. Epub 2024 Jul 16.
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 , the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound with a 5.6-fold improvement in Hsp70-Bim PPI suppression ( = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 μg/mL) compared to . It maintains comparable apoptosis induction capability with against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, H-N 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.
热休克蛋白 70- Bim 蛋白-蛋白相互作用（PPI）是慢性髓系白血病（CML）治疗中最近确定的特定靶点。在此，我们通过 的骨架跃迁开发了一类新型热休克蛋白 70-Bim PPI 抑制剂，这是迄今为止最有效的热休克蛋白 70-Bim PPI 抑制剂。通过构效关系（SAR）研究，我们获得了一种联苯骨架化合物 ，与 相比，其对热休克蛋白 70-Bim PPI 的抑制作用提高了 5.6 倍（ = 123 对 688 nM），水溶性提高了 4 倍（29.42 对 7.19 μg/mL）。与 相比，它以热休克蛋白 70-Bim 依赖的方式保持了对 TKI 敏感和 TKI 耐药 CML 细胞系类似的凋亡诱导能力。此外，通过 SAR、H-N TRSOY-NMR 和分子对接，我们揭示了 Lys319 是热休克蛋白 70-Bim PPI 界面的“热点”。总之，这些结果为热休克蛋白 70-Bim PPI 抑制剂的合理设计提供了新的化学骨架和结构见解。
