title: Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities.
abstract: In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed and colocalize with the androgen receptor. We designed and synthesized hybrid LSD1/JmjC or "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, 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 noncancer mesenchymal progenitor (MePR) cells, 2 and 3 induced little and no apoptosis, respectively, thus showing cancer-selective inhibiting action.
authors: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P. le A. Moro 5, 00185 Rome, Italy.
authors: Dante
authors: D
authors: Rotili
authors: Stefano
authors: S
authors: Tomassi
authors: Mariarosaria
authors: M
authors: Conte
authors: Rosaria
authors: R
authors: Benedetti
authors: Marcello
authors: M
authors: Tortorici
authors: Giuseppe
authors: G
authors: Ciossani
authors: Sergio
authors: S
authors: Valente
authors: Biagina
authors: B
authors: Marrocco
authors: Donatella
authors: D
authors: Labella
authors: Ettore
authors: E
authors: Novellino
authors: Andrea
authors: A
authors: Mattevi
authors: Lucia
authors: L
authors: Altucci
authors: Anthony
authors: A
authors: Tumber
authors: Clarence
authors: C
authors: Yapp
authors: Oliver N F
authors: ON
authors: King
authors: Richard J
authors: RJ
authors: Hopkinson
authors: Akane
authors: A
authors: Kawamura
authors: Christopher J
authors: CJ
authors: Schofield
authors: Antonello
authors: A
authors: Mai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases