TY - JOUR
T1 - A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth
AU - Wang, Lei
AU - Chang, Jianjun
AU - Varghese, Diana
AU - Dellinger, Michael
AU - Kumar, Subodh
AU - Best, Anne M.
AU - Ruiz, Julio
AU - Bruick, Richard
AU - Peña-Llopis, Samuel
AU - Xu, Junjie
AU - Babinski, David J.
AU - Frantz, Doug E.
AU - Brekken, Rolf A.
AU - Quinn, Amy M.
AU - Simeonov, Anton
AU - Easmon, Johnny
AU - Martinez, Elisabeth D.
PY - 2013/6/24
Y1 - 2013/6/24
N2 - The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.
AB - The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.
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U2 - 10.1038/ncomms3035
DO - 10.1038/ncomms3035
M3 - Article
C2 - 23792809
AN - SCOPUS:84889595831
VL - 4
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2035
ER -