Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 1, Pages 42-55Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4012802
Keywords
-
Categories
Funding
- FIRB RBFR10ZJQT
- Sapienza Ateneo Project
- IIT-Sapienza Project
- Fondazione Cariplo [2010.0778]
- AIRC [IG-11342, IG-11812]
- MIUR (Progetto Epigen)
- FP7 Project [BLUEPRINT/282510]
- [COST/TD0905]
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available