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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chang
authors.forename: Diana
authors.initials: D
authors.lastname: Varghese
authors.forename: Michael
authors.initials: M
authors.lastname: Dellinger
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
authors.forename: Anne M
authors.initials: AM
authors.lastname: Best
authors.forename: Julio
authors.initials: J
authors.lastname: Ruiz
authors.forename: Richard
authors.initials: R
authors.lastname: Bruick
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.forename: Junjie
authors.initials: J
authors.lastname: Xu
authors.forename: David J
authors.initials: DJ
authors.lastname: Babinski
authors.forename: Doug E
authors.initials: DE
authors.lastname: Frantz
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Amy M
authors.initials: AM
authors.lastname: Quinn
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Johnny
authors.initials: J
authors.lastname: Easmon
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Martinez
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D007536:Isomerism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006657:Histones; D006835:Hydrazones; C585278:JIB-04; D054852:Small Molecule Libraries; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine