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 and Elisabeth D. Martinez ()
Additional contact information
Lei Wang: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Jianjun Chang: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Diana Varghese: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Michael Dellinger: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Subodh Kumar: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Anne M. Best: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Julio Ruiz: UT Southwestern Medical Center at Dallas
Richard Bruick: UT Southwestern Medical Center at Dallas
Samuel Peña-Llopis: UT Southwestern Medical Center at Dallas
Junjie Xu: UT Southwestern Medical Center at Dallas
David J. Babinski: UT Southwestern Medical Center at Dallas
Doug E. Frantz: UT San Antonio
Rolf A. Brekken: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas
Amy M. Quinn: NIH Chemical Genomics Center, National Institutes of Health
Anton Simeonov: NIH Chemical Genomics Center, National Institutes of Health
Johnny Easmon: Leopold-Franzens University
Elisabeth D. Martinez: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms3035 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3035

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms3035

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().