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

Lei Wang, Jianjun Chang, Diana Varghese, Michael Dellinger, Subodh Kumar, Anne M. Best, Julio Ruiz, Richard Bruick, Samuel Peña-Llopis, Junjie Xu, David J. Babinski, Doug E. Frantz, Rolf A. Brekken, Amy M. Quinn, Anton Simeonov, Johnny Easmon, Elisabeth D. Martinez

Research output: Contribution to journalArticlepeer-review

226 Scopus citations


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 languageEnglish (US)
Article number2035
JournalNature communications
StatePublished - Jun 24 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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