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.

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.

01 Sep 2024·Biomedicine & Pharmacotherapy

Synthesis and biological evaluation of imidazolium conjugated with dimethylcardamonin (DMC) as a novel potential agent against MDA-MB-231 triple-negative breast cancer cells

Article

Author: Utama, Kraikrit ; Siriphong, Sadanon ; Khamto, Nopawit ; Chawapun, Pornthip ; Meepowpan, Puttinan ; Kantapan, Jiraporn ; Dechsupa, Nathupakorn ; Sangthong, Padchanee ; Meerak, Jomkhwan

A new imidazolium ionic liquid (IL) halide conjugated with dimethylcardamonin (DMC, 1), namely [Bbim]Br-DMC (3), was synthesised to improve the biological activity of the natural chalcone. DMC was isolated from seeds of Syzygium nervosum A. Cunn. ex DC. which was an effective anti-breast cancer agent. The compound 1 and 3 showed anticancer activity in MDA-MB-231 cells with IC₅₀ values of 14.54 ± 0.99 μM and 7.40 ± 0.15 μM, respectively. MTT assay showed that compound 3 had cytotoxic effect at least two-fold greater than compound 1 but was low toxic to normal cells of Hs 578Bst. After 48 h, compound 3 at concentration of IC₅₀ value inhibited the proliferation and induced morphological changes of MDA-MB-231 cells in a time-dependent manner. The cell cycle profile also showed that compound 3 exerted anti-proliferation activity with the cell cycle arrest at G0/G1 phase and compound 3 also induced apoptosis and reduced mitochondrial membrane potential in MDA-MB-231 cells in a dose-dependent manner. In gene expression assay, compound 3 up-regulated pro-apoptotic genes such as Bax and p53 and suppressed anti-apoptotic Bcl-2 whereas there was no effect on DNA repair gene such as PARP1. The Bax/Bcl-2 ratio was significantly increased after treated with compound 3. In the molecular docking study, the interactions between compound 3 and B-DNA structure in the minor groove region via hydrogen bonds was reported. In conclusion, [Bbim]Br-DMC or compound 3 is a potential candidate to induce apoptosis and inhibits proliferation via cell cycle arrest and decreases mitochondrial membrane of triple-negative breast cancer MDA-MB-231 cells.

100 Deals associated with KRAS G12R inhibitors(The University of California, San Francisco)

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	US	The University of California, San Francisco	28 Sep 2022
Pancreatic Cancer	Preclinical	US	The University of California, San Francisco	28 Sep 2022

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