ArticleThe Journal of biological chemistry2014
Novel piperazine-based compounds inhibit microtubule dynamics and sensitize colon cancer cells to tumor necrosis factor-induced apoptosis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 44 citations in OpenAlex.
- Innovative horizons: harnessing drug repositioning for targeted therapeutics in colorectal cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Green Approach Toward Triazole Forming Reactions for Developing Anticancer Drugs.Current organic synthesis · 2024Review
- Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Discovery of Simple Diacylhydrazine-Functionalized Cinnamic Acid Derivatives as Potential Microtubule Stabilizers.International journal of molecular sciences · 2022Article
- Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis.Translational oncology · 2022Article
- A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization.International journal of molecular sciences · 2022Review
- Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Design and synthesis of substituted (1-(benzyl)-1RSC medicinal chemistry · 2020Article
- Drug Repositioning of the αInternational journal of molecular sciences · 2020Review
- Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System.International journal of molecular sciences · 2020Review
- Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy.Medicinal research reviews · 2019Review
- Spindle Assembly Disruption and Cancer Cell Apoptosis with a CLTC-Binding Compound.Molecular cancer research : MCR · 2018Article
- Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy.BioMed research international · 2018Article
- Design and synthesis of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-2H-1,2,3-triazole derivatives as colchicine binding site inhibitors.Scientific reports · 2017Article
- Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule.Oncotarget · 2017Article
- Theoretical and experimental study of polycyclic aromatic compounds as β-tubulin inhibitors.Journal of molecular modeling · 2017Article
- Article
- Colchicine Significantly Reduces Incident Cancer in Gout Male Patients: A 12-Year Cohort Study.Medicine · 2015Observational
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
We recently identified a series of mitotically acting piperazine-based compounds that potently increase the sensitivity of colon cancer cells to apoptotic ligands. Here we describe a structure-activity relationship study on this compound class and identify a highly active derivative ((4-(3-chlorophenyl)piperazin-1-yl)(2-ethoxyphenyl)methanone), referred to as AK301, the activity of which is governed by the positioning of functional groups on the phenyl and benzoyl rings. AK301 induced mitotic arrest in HT29 human colon cancer cells with an ED50 of ≈115 nm. Although AK301 inhibited growth of normal lung fibroblast cells, mitotic arrest was more pronounced in the colon cancer cells (50% versus 10%). Cells arrested by AK301 showed the formation of multiple microtubule organizing centers with Aurora kinase A and γ-tubulin. Employing in vitro and in vivo assays, tubulin polymerization was found to be slowed (but not abolished) by AK301. In silico molecular docking suggests that AK301 binds to the colchicine-binding domain on β-tubulin, but in a novel orientation. Cells arrested by AK301 expressed elevated levels of TNFR1 on their surface and more readily activated caspases-8, -9, and -3 in the presence of TNF. Relative to other microtubule destabilizers, AK301 was the most active TNF-sensitizing agent and also stimulated Fas- and TRAIL-induced apoptosis. In summary, we report a new class of mitosis-targeting agents that effectively sensitizes cancer cells to apoptotic ligands. These compounds should help illuminate the role of microtubules in regulating apoptotic ligand sensitivity and may ultimately be useful for developing agents that augment the anti-cancer activities of the immune response.
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