title: A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1.
abstract: The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure-activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μM). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.
authors: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).
authors: Rachel
authors: R
authors: Schiller
authors: Giuseppe
authors: G
authors: Scozzafava
authors: Anthony
authors: A
authors: Tumber
authors: James R
authors: JR
authors: Wickens
authors: Jacob T
authors: JT
authors: Bush
authors: Ganesha
authors: G
authors: Rai
authors: Clarisse
authors: C
authors: Lejeune
authors: Hwanho
authors: H
authors: Choi
authors: Tzu-Lan
authors: TL
authors: Yeh
authors: Mun Chiang
authors: MC
authors: Chan
authors: Bryan T
authors: BT
authors: Mott
authors: James S O
authors: JS
authors: McCullagh
authors: David J
authors: DJ
authors: Maloney
authors: Christopher J
authors: CJ
authors: Schofield
authors: Akane
authors: A
authors: Kawamura
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D006912:Hydroxyquinolines; D056484:Jumonji Domain-Containing Histone Demethylases; C000592885:5-carboxy-8-hydroxyquinoline
keywords: 2-oxoglutarate (2OG) oxygenases; cell permeability; epigenetics; inhibitors; jmjc histone demethylases; structure-activity relationships