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Ref Type Journal Article
PMID (23792809)
Authors Wang L, Chang J, Varghese D, Dellinger M, Kumar S, Best AM, Ruiz J, Bruick R, Peña-Llopis S, Xu J, Babinski DJ, Frantz DE, Brekken RA, Quinn AM, Simeonov A, Easmon J, Martinez ED
Title A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth.
Journal Nature communications
Vol 4
Issue
Date 2013
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
JIB-04 JIB-04 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JIB-04 JIB-04 is a selective small molecule inhibitor of the histone demethylases KDM4A, KDM4B, KDM4C, KDM4D, KDM4E, KDM5A, and KDM6B, demonstrating specific activity in cancer cells not seen in matched normal controls, and also induced transcriptional changes reducing cellular proliferation and promoting apoptosis of cancer cells (PMID: 23792809, PMID: 32581546).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable JIB-04 Preclinical Actionable In a preclinical study, JIB-04, a pan Jumonji histone demethylase inhibitor, reduced cell proliferation, and induced apoptosis in multiple cancer cell types while reducing tumor burden and increasing survival in mouse xenograft models (PMID: 23792809). 23792809