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Pan-histone demethylase inhibitors simultaneously targeting Jumonji C and lysine-specific demethylases display high anticancer activities

Lookup NU author(s): Professor Akane Kawamura


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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. © 2013 American Chemical Society.

Publication metadata

Author(s): Rotili D, Tomassi S, Conte M, Benedetti R, Tortorici M, Ciossani G, Valente S, Marrocco B, Labella D, Novellino E, Mattevi A, Altucci L, Tumber A, Yapp C, King ONF, Hopkinson RJ, Kawamura A, Schofield CJ, Mai A

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2014

Volume: 57

Issue: 1

Pages: 42-55

Print publication date: 09/01/2014

Online publication date: 10/12/2013

Acceptance date: 19/08/2013

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm4012802

PubMed id: 24325601


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