Pan-Histone Demethylase Inhibitors Simultaneously Targeting Jumonji C and Lysine-Specific Demethylases Display High Anticancer Activities

• DOI: 10.1021/jm4012802
• Publication Date: 2013-12-10T21:08:58Z
• Authors: Dante Rotili; Stefano Tomassi; Mariarosaria Conte; Rosaria Benedetti; Marcello Tortorici; Giuseppe Ciossani; Sergio Valente; Biagina Marrocco; Donatella Labella; Ettore Novellino; Andrea Mattevi; Lucia Altucci; Anthony Tumber; Clarence Yapp; Oliver N. F. King; Richard J. Hopkinson; Akane Kawamura; Christopher J. Sc...; Antonello Mai
• Keywords: Histone Demethylases; 0301 basic medicine; 570; Jumonji Domain-Containing Histone Demethylases; Inhibitors; 610; Antineoplastic Agents; Apoptosis; Pan-Histone Demethylase; Jumonji C; prostate cancer; Cancer; KDM; epigenetics; Pan-Histone Demethylase, Jumonji C, Inhibitors, prostate cancer,; Drug design; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Cell Line, Tumor; Humans; Epigenetics; Enzyme Inhibitors

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.