Exploiting the "Hot-Spots" of Hsp70 - Bim Protein - Protein Interaction to Optimize the 1-Oxo-1 H -phenalene-2,3-dicarbonitrile Analogues as Specific Hsp70 - Bim Inhibitors

• Published in: Journal of medicinal chemistry 2023-12, Vol.66 (23), p.16377-16387
• Main Authors: Wang, Ziqian, Zhang, Hong, Li, Xin, Song, Yang, Wang, Yuying, Hu, Zhiyuan, Gao, Qishuang, Jiang, Maojun, Yin, Fangkui, Yuan, Linjie, Liu, Jingjing, Song, Ting, Lu, Shaohua, Xu, Guanghong, Zhang, Zhichao
• Format: Article
• Language: English
• Subjects: Apoptosis; Bcl-2-Like Protein 11 - metabolism; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - metabolism; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - metabolism; Imatinib Mesylate - pharmacology; Protein Kinase Inhibitors - pharmacology; Signal Transduction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01783

Selectively targeting the cancer-specific protein protein interaction (PPI) between Hsp70 and Bim has been discovered as a promising strategy for treating chronic myeloid leukemia (CML). The first Hsp70 Bim PPI inhibitor, , has been identified to overcome the on-target toxicity of known Hsp70 inhibitors when it induces apoptosis of CML cells. Herein, we carried out a hit-to-lead optimization of , yielding , which exhibited a 10-fold increase in Hsp70/Bim suppressing potency. Furthermore, not only exhibited a 5- to 10-fold stronger antitumor activity in the sub-μM range against CML cells than in vitro, but it also overcame BCR-ABL-independent tyrosine kinase inhibitor resistance in CML in vivo depending on the Hsp70 Bim signaling pathway. Moreover, through structure activity relationship analysis, TROSY-HSQC NMR, molecular dynamics simulation, and point mutation validation, two hydrophobic pockets composed of eight key residues were demonstrated to produce predominant interactions with either Bim or , regarded as the "hot-spots" in the Hsp70 Bim PPI interface.