This study explores the potential of nitro compounds as inhibitors of Carbonic Anhydrase IX (CAIX) for cancer therapy. Molecular docking and virtual screening were employed to identify lead molecules, focusing on their binding affinities and interactions with CAIX. Six compounds, namely D1 (-8.295 kcal/mol), D2 (-10.980 kcal/mol), D3 (-10.963 kcal/mol), D4 (-7.170 kcal/mol), D5 (-7.368 kcal/mol), and D6 (-8.705 kcal/mol), were selected based on their promising docking scores and Molecular Mechanics-Generalized Born Surface Area (MMGBSA) results. Molecular dynamics simulations further confirmed the stability of the CAIX-lead compound complexes, with low root-mean-square deviation (RMSD) values and minimal fluctuations in protein and ligand structures. The analysis of root-mean-square fluctuations (RMSF) highlighted the overall stability of these complexes, with localized fluctuations. Detailed investigation of protein-ligand contact dynamics unveiled strong and consistent interactions, including hydrogen bonds, ionic interactions, water bridges, and salt bridges. These novel interactions shed light on the dynamic behavior of the CAIX-lead compound complexes. Briefly, this study establishes a robust framework for advancing D1, D2, and D3 as promising CAIX inhibitors in cancer treatment. The meticulous analysis and comprehensive approach applied to these primary compounds yield substantial insights into their potential as therapeutic agents, setting the stage for forthcoming experimental validation and clinical utilization.

2025-12-01·JOURNAL OF CONTROLLED RELEASE

Tailored mechano-responsive micelles mimic the iron starvation response and impair pH homeostasis for triggered cancer therapy

Article

作者: Leng, Hongyu ; Li, Xin ; Du, Panyu ; Wang, Han ; Li, Yao ; Zhao, Ning ; Zhao, Yanjun ; Wang, Zheng ; Li, Huikai

Carbonic anhydrase IX (CAIX) and cysteine desulfurase (NFS1) are a synthetic lethal pair for cancer treatment. The suppression of NFS1 upregulates the iron starvation response and enriches intracellular Fe²⁺, leading to increased lipid peroxidation. However, the potency of the NFS1 inhibitor is compromised by the hypoxic microenvironment. To address this issue, we report a mechano-responsive ferrocene-bearing micelle that mimics the CAIX/NFS1 axis via ultrasound-activated iron release and the co-delivery of SLC-0111, a CAIX inhibitor. Upon ultrasound stimulation, the micelles disassemble in acidic lysosomes, releasing ferrous ions and SLC-0111, triggering intracellular acidification, reactive oxygen species accumulation, and lipid peroxidation. Moreover, the liberation of Fe²⁺ is facilitated by the presence of hydrogen peroxide and further enhanced by mechanical force. SLC-0111 leads to intracellular acidification and synergizes with Fe²⁺ to boost the Fenton reaction. This cascade disrupted redox homeostasis and induced multiple cell death pathways, including ferroptosis, apoptosis, pyroptosis, and necroptosis, in a tumor-selective manner. The in vivo efficacy studies in a 4T1 breast cancer model confirmed potent tumor suppression with minimal systemic toxicity. This work introduces a mechanical force-controlled strategy as a substitute for CAIX/NFS1 synthetic lethality therapy without the interference of oxygen level, holding promise for advancing tumor-specific therapy.

2025-11-25·ZEITSCHRIFT FUR NATURFORSCHUNG SECTION C-A JOURNAL OF BIOSCIENCES

Design and synthesis of 3-(azepan-1-ylsulfonyl)- N -aryl benzamide derivatives as potent carbonic anhydrase IX inhibitors with anticancer activities

Article

作者: Khanfar, Mohammad A. ; Saleh, Mohammad

Abstract:

Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression. A series of 3-sulfonamide benzoate derivatives with a 7-membered azepane ring were synthesized and evaluated for their CAIX inhibitory activities. Most of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC 50 values in the low nanomolar range. The most potent CAIX inhibitor was compound 26 , with an IC 50 of 19 nM. A structure-activity relationship analysis of the synthesized compounds was conducted, and molecular docking revealed strong coordination with the catalytic Zn 2+ metal, hydrophobic interactions of the azepane ring with a hydrophobic pocket, and π-stacking interactions of the aryl ring with an aromatic surface. The three most active analogues ( 8 , 16 , and 26 ) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines screen. Notably, compound 16 (CAIX, IC 50 = 310 nM) demonstrated potent growth inhibitory effects against several cancer cell lines.

100 项与 CA9抑制剂(NRC) 相关的药物交易

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