Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities
| Autor: | Donatella Labella, Lucia Altucci, Anthony Tumber, Biagina Marrocco, Clarence Yapp, Giuseppe Ciossani, Dante Rotili, Oliver N. King, Marcello Tortorici, Sergio Valente, Richard J. Hopkinson, Stefano Tomassi, Mariarosaria Conte, Andrea Mattevi, Akane Kawamura, Ettore Novellino, Rosaria Benedetti, Antonello Mai, Christopher J. Schofield |
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| Přispěvatelé: | Rotili, D, Tomassi, S, Conte, M, Benedetti, R, Tortorici, M, Ciossani, G, Valente, S, Marrocco, B, Labella, D, Novellino, E, Mattevi, A, Altucci, Lucia, Tumber, A, Yapp, C, King, On, Hopkinson, Rj, Kawamura, A, Schofield, Cj, Mai, A., Dante, Rotili, Tomassi, Stefano, Mariarosaria, Conte, Rosaria, Benedetti, Marcello, Tortorici, Giuseppe, Ciossani, Sergio, Valente, Biagina, Marrocco, Donatella, Labella, Novellino, Ettore, Andrea, Mattevi, Lucia, Altucci, Anthony, Tumber, Clarence, Yapp, King, Oliver N. F., Hopkinson, Richard J., Akane, Kawamura, Schofield, Christopher J., Antonello, Mai |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Jumonji Domain-Containing Histone Demethylases
Lysine Antineoplastic Agents Apoptosis Pan-Histone Demethylase Jumonji C Inhibitors prostate cancer KDM Structure-Activity Relationship Prostate cancer Cell Line Tumor Drug Discovery LNCaP medicine Humans Enzyme Inhibitors Cancer Histone Demethylases biology epigenetics Chemistry Tranylcypromine medicine.disease 3. Good health Molecular Docking Simulation Androgen receptor Histone Biochemistry biology.protein Cancer research Molecular Medicine Demethylase medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry; Vol 57 Journal of Medicinal Chemistry Journal of medicinal chemistry 57 (2014): 42–55. doi:10.1021/jm4012802 info:cnr-pdr/source/autori:Rotili, Dante; Tomassi, Stefano; Conte, Mariarosaria; Benedetti, Rosaria; Tortorici, Marcello; Ciossani, Giuseppe; Valente, Sergio; Marrocco, Biagina; Labella, Donatella; Novellino, Ettore; Mattevi, Andrea; Altucci, Lucia; Tumber, Anthony; Yapp, Clarence; King, Oliver N. F.; Hopkinson, Richard J.; Kawamura, Akane; Schofield, Christopher J.; Mai, Antonello/titolo:Pan-Histone Demethylase Inhibitors Simultaneously Targeting Jumonji C and Lysine-Specific Demethylases Display High Anticancer Activities/doi:10.1021%2Fjm4012802/rivista:Journal of medicinal chemistry/anno:2014/pagina_da:42/pagina_a:55/intervallo_pagine:42–55/volume:57 |
| DOI: | 10.1021/jm4012802 |
| Popis: | In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are co-expressed and co-localize with the androgen receptor. We designed and synthesized hybrid LSD1/JmjC - "pan-KDM" - inhibitors 1-6, by coupling the skeleton of tranylcypromine 7, a known LSD1 inhibitor, with 4-carboxy-4'-carbomethoxy-2,2'-bipyridine 8 or 5-carboxy-8-hydroxyquinoline 9, two 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds 1-6 are able to simultaneously target both KDM families, and have been validated as potential antitumor agents in cells. Among them, compounds 2 and 3 increase H3K4 and H3K9 methylation levels in cells and cause growth arrest and substantial apoptosis in LNCaP prostate and HCT116 colon cancer cells. When tested in non-cancer mesenchymal progenitor (MePR) cells, 2 and 3 induced little and no apoptosis, respectively, thus showing a cancer-selective inhibiting action. |
| Databáze: | OpenAIRE |
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