Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 2035 |
| Journal | Nature Communications |
| Volume | 4 |
| State | Published - 2013 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Chemistry(all)
- Physics and Astronomy(all)
- Medicine(all)
Cite this
A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. / Wang, Lei; Chang, Jianjun; Varghese, Diana; Dellinger, Michael; Kumar, Subodh; Best, Anne M.; Ruiz, Julio; Bruick, Richard; Peña-Llopis, Samuel; Xu, Junjie; Babinski, David J.; Frantz, Doug E.; Brekken, Rolf A.; Quinn, Amy M.; Simeonov, Anton; Easmon, Johnny; Martinez, Elisabeth D.
In: Nature Communications, Vol. 4, 2035, 2013.Research output: Contribution to journal › Article
}
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
Y1 - 2013
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.
UR - http://www.scopus.com/inward/record.url?scp=84889595831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84889595831&partnerID=8YFLogxK
M3 - Article
C2 - 23792809
AN - SCOPUS:84889595831
VL - 4
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2035
ER -