@article{2caff6a061f241edb9ba207642bedbae,
title = "A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth",
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.",
author = "Lei Wang and Jianjun Chang and Diana Varghese and Michael Dellinger and Subodh Kumar and Best, {Anne M.} and Julio Ruiz and Richard Bruick and Samuel Pe{\~n}a-Llopis and Junjie Xu and Babinski, {David J.} and Frantz, {Doug E.} and Brekken, {Rolf A.} and Quinn, {Amy M.} and Anton Simeonov and Johnny Easmon and Martinez, {Elisabeth D.}",
note = "Funding Information: We are deeply indebted to Drs David J. Mangelsdorf and John D. Minna for generous sharing of resources, insightful discussions and general project support. We are grateful to Drs A. Smith and J. Richardson for assistance with histology, Drs C. Cummins and Z. Wang for help with mass spectrometry, and Dr A. Jadhav for compound informatics. Cell lines were kindly provided by Dr J. Minna, Dr C. Lewis, Dr D. Euhus and Dr J.T. Hsieh. We are grateful to Dr Luc Girard for the gift of the DIVISA and Matrix software. We thank Dr S. Vega-Rubin-de-Celis, Dr K. Gardner, Dr T. Scheuermann, Dr S. Hoffman, Dr S. Kliewer, Dr C.M. Chiang, Dr H. Yu, Dr J. Rizo-Rey, Dr Sam John, Dr E. Komives and members of the Minna and Mangelsdorf/Kliewer laboratories for helpful discussions. J.C.R. is a Howard Hughes Medical Institute Scholar and was supported by a Sara and Frank McKnight Graduate Student Fellowship. R.K.B. is the Michael L. Rosenberg Scholar in Medical Research and was supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund and the NCI (CA095471). This investigation was partly conducted in a facility constructed with support from the Research Facilities Improvement Program (Grant # C06 RR 15437-01) from the NCRR, NIH. This project was partly funded by the NCI (K22CA11871703 and R01CA12526901 to E.D.M.), by the DoD (W81XWH0910365 to E.D.M.), by the University of Texas SPORE in Lung Cancer (P50-CA70907 to J.D.M.) and by the DCF (Nolan Miller Lung Cancer grant to E.D.M.). The authors acknowledge the assistance of the Genomics Shared Resource at the Harold C. Simmons Cancer Center, which is supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2013 Macmillan Publishers Limited. All rights reserved.",
year = "2013",
month = jun,
day = "24",
doi = "10.1038/ncomms3035",
language = "English (US)",
volume = "4",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}