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Nat Commun. 2013;4:2035. doi: 10.1038/ncomms3035.

A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth.

Author information

1
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

Erratum in

  • Nat Commun. 2013;4:2639.

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.

PMID:
23792809
PMCID:
PMC3724450
DOI:
10.1038/ncomms3035
[Indexed for MEDLINE]
Free PMC Article

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