Author: Skok, Žiga ; Goričan, Tjaša ; Ilaš, Janez ; Sturtzel, Caterina ; Distel, Martin ; Zidar, Nace ; Zajec, Živa ; Golič Grdadolnik, Simona ; Gedgaudas, Marius ; Dernovšek, Jaka ; Urbančič, Dunja ; Grissenberger, Sarah ; Wenninger-Weinzierl, Andrea ; Tomašič, Tihomir ; Zubrienė, Asta

Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain. Nineteen analogs were then prepared and evaluated to investigate the structure-activity relationships, several of which inhibited the growth of SK-N-MC Ewing sarcoma cells in vitro. Compound 3 emerged as one of the most potent growth inhibitors (IC₅₀ = 0.33 ± 0.04 µM), demonstrating the ability to induce apoptosis and cell cycle arrest in SK-N-MC cells in vitro, and to slow the growth of Ewing sarcoma in vivo in a zebrafish model.

26 Nov 2024·Analytical Chemistry

Dual-Locked Chemiluminescent Probe Enables Precise Imaging and Timely Diagnosis of Colitis via Chymotrypsin/Vanin-1 Cascade Activation

Article

Author: Cao, Gao-Yao ; Xu, Si-Tao ; Wang, Guangji ; Jin, Xin ; Zhen, Le ; Chen, De-Ao ; Wang, Jiankun ; Xie, Tao ; Wang, Qi

The development of precise diagnosis and the discovery of individualized drugs go together to provide effective therapy against inflammatory bowel disease (IBD). The exploitation of the unique imaging advantages of chemiluminescent probes represents a pivotal strategy for achieving this goal. Nevertheless, the dual-locked strategy, which is believed to enhance precision, is rarely employed in the design of chemiluminescent probes. A novel dual-locked chemiluminescent probe, BPan-CL, was designed based on IBD candidate biomarkers chymotrypsin (CHT) and vanin-1. BPan-CL exhibited specific reactivity and chemiluminescence response when subjected to simultaneous stimulation of CHT and vanin-1, with a signal-to-noise ratio superior to that of the fluorescent probe with the same dual-locked mode. In both live cell and IBD mice imaging, BPan-CL demonstrated superior sensitivity compared to its single-locked counterpart, Pan-CL. In contrast to Pan-CL, BPan-CL was able to more accurately identify IBD and healthy mice by in vivo imaging and allowed for early prediction of IBD using a noninvasive fecal test. BPan-CL has identified CHT and vanin-1 as valuable combinatorial biomarkers for accurate and early IBD diagnosis. This strategy has significant potential for use in biomedical imaging and future individualized therapies.

01 Sep 2024·Chemistry & Biodiversity

Discovery of Sesquiterpene Lactones with Cytotoxicity from the Herb of Youngia japonica

Article

Author: Lin, Kuan ; Gui, Yu-Ran ; Zhu, Shu‐Xiu ; Sun, Bin-Lian ; Zhou, Le ; Chen, Hai‐Feng ; Sun, Bin‐Lian ; Shu, Xi-Ji ; Shang, Jin-Ting ; Shang, Jin‐Ting ; Tao, Xiao‐Qing ; Ye, Xian-Sheng ; Tao, Xiao-Qing ; Shu, Xi‐Ji ; Chen, Hai-Feng ; Xia, Yi‐Yuan ; Liu, Wei ; Gui, Yu‐Ran ; Zhu, Shu-Xiu ; Ye, Xian‐Sheng ; Xia, Yi-Yuan

AbstractIn the process of searching for anti‐breast cancer agents, five sesquiterpene lactones (1‐5), including two previously undescribed ones, yjaponica B‐C (1‐2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC50 value of 10.60 μM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl‐2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti‐breast cancer agent.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Preclinical	United States	Pfizer Inc.	17 Jan 2022

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