Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3035
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Funding
- Sara and Frank McKnight Graduate Student Fellowship
- Burroughs Wellcome Fund
- NCI [CA095471, K22CA11871703, R01CA12526901]
- NCRR, NIH [C06 RR 15437-01]
- DoD [W81XWH0910365]
- University of Texas SPORE in Lung Cancer [P50-CA70907]
- DCF (Nolan Miller Lung Cancer grant)
- NCI Cancer Center [1P30 CA142543-01]
- U.S. Department of Defense (DOD) [W81XWH0910365] Funding Source: U.S. Department of Defense (DOD)
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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 alpha-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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