作者: Wen, Yan-Qing ; Zhang, Xu ; Li, Ting-Ting ; Guo, Shuai ; Zhang, Ting-Jian ; Wang, Yan-Ping ; Zhang, Yi ; Wang, Qiu-Yin ; Zheng, Yi-Meng ; Meng, Fan-Hao

A series of 2-benzyl-4-substituted-2-azabicyclo[3.2.1]octanes, derived from the E-F ring of aconitine scaffold, were designed as potential anticancer agents. Utilizing two key reactions, asymmetric aza-Diels-Alder addition and S_N2 type ring expansion, to construct the core bicyclic skeleton, forty-one target compounds (11a-v and 13a-s) were successfully synthesized. Most of the target compounds exhibited considerable antiproliferative effects against four cancer cell lines (A549, HT-29, HepG2 and MDA-MB 231) with low IC₅₀ values. Among them, compound 13l showed the most potent antiproliferative activity against HT-29 colorectal cancer (CRC) cells, and displayed significant heat shock protein 90 (Hsp90) inhibitory activity. Molecular modeling studies supported the experimental results and the key interactions were identified. Further investigation indicated that 13l could effectively suppress the proliferation and migration of HT-29 cells, along with inducing cell cycle arrest and mild apoptosis via down-regulation of CDK12, CDK13 and Bcl-2 protein expressions, and up-regulation of Bax. Mechanistic studies revealed that 13l could inhibit Hsp90 to destabilize EGFR and suppress the activation of the EGFR-Akt signaling pathway to reduce proliferation of HT-29 cells. Consistent with in vitro results, 13l significantly repressed tumor growth in an HT-29 xenograft mouse model without causing evident cytotoxicity. Therefore, 13l could be considered as a novel and potentially effective candidate for the future treatment of CRC.

2025-07-01·ANTICANCER RESEARCH

Tetrahydroindazolone-substituted Benzamide Compound W-H4 Induces Apoptosis and Autophagy of Acute Myeloid Leukemia Cells

Article

作者: Liu, Zhong ; Li, Yawen ; Wang, Sheng ; Wang, Han ; Zou, Jiahua ; Qian, Chuiwen

BACKGROUND/AIM:

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Hsp90 inhibitors, like SNX-2112, are promising anti-cancer agents. However, SNX-2112's clinical use is limited by poor solubility and side effects. This study aimed to improve tetrahydroindazolone-substituted benzamide compounds and to investigate its mechanism of action against AML cells.

MATERIALS AND METHODS:

The anti-proliferative effects of nine tetrahydroindazolone-substituted benzamide derivatives were evaluated across eight cancer cell lines using the CCK-8 assay. W-H4 was identified as the most potent compound and further investigated for its effects on acute myeloid leukemia (AML) cells. Analyses of apoptosis, autophagy, and cell cycle arrest were conducted using flow cytometry and Western blotting, while mitochondrial membrane potential (MMP) was assessed via JC-1 staining.

RESULTS:

W-H4, a tetrahydroindazolone-substituted benzamide, effectively inhibited the proliferation of acute myeloid leukemia (AML) cells in vitro. The compound destabilized Hsp90 client proteins and induced autophagy, as indicated by LC3-II accumulation. Additionally, W-H4 caused G₀/G₁ cell cycle arrest and triggered both caspase-dependent and intrinsic apoptosis, accompanied by modulation of Bcl-2 family proteins and a decrease in mitochondrial membrane potential. These results highlight W-H4's potential as a therapeutic agent for AML treatment.

CONCLUSION:

W-H4 emerges as a potential Hsp90 inhibitor, providing novel therapeutic opportunities for the targeted treatment of acute myeloid leukemia.

2025-05-26·Journal of Chemical Information and Modeling

Dual-Site Targeting by Peptide Inhibitors of the N-Terminal Domain of Hsp90: Mechanism and Design

Article

作者: Zhou, Xuejie ; Wang, Lei ; Dong, Hao ; Zang, Min ; Gan, Haipeng

Heat shock protein 90 (Hsp90) is a pivotal molecular chaperone crucial in the maturation of client proteins, positioning it as a significant target for cancer therapy. However, the design of effective Hsp90 inhibitors presents substantial challenges due to the complex interaction network and the requisite specificity of the inhibitors. This study tackles the task of designing peptide inhibitors capable of concurrently binding to both the ATP-binding pocket and the Cdc37-binding site within the N-terminal domain of Hsp90. In response to these challenges, we developed an advanced peptide screening protocol that merges machine learning with various molecular simulation techniques to boost the identification and optimization of potent inhibitors. Our integrated approach employs a convolutional neural network-based framework to predict peptide binding propensities. This predictive model is augmented by comprehensive molecular docking and dynamic simulations to assess the stability and interaction dynamics of Hsp90/peptide complexes. We successfully identified three heptapeptides that demonstrate the ability to interact with both binding sites, effectively obstructing the entrance to the ATP-binding pocket. This study elucidates the inhibitory mechanisms of these peptides, paves the way for the development of more efficacious therapeutic agents targeting Hsp90, and underscores the value of integrating machine learning techniques with molecular modeling in the peptide design process.

100 项与 Hsp90 Inhibitors(National Academy of Sciences of Belarus) 相关的药物交易

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