A cell-permeable ester derivative of the JmjC histone demethylase inhibitor IOX1
| Autor: | Rachel Schiller, Jacob T. Bush, G Scozzafava, James Wickens, Ganesha Rai, Bryan T. Mott, Akane Kawamura, Anthony Tumber, Clarisse Lejeune, Mun Chiang Chan, Tzu-Lan Yeh, James S. O. McCullagh, Hwanho Choi, David J. Maloney, Christopher J. Schofield |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Oxygenase Jumonji Domain-Containing Histone Demethylases Cell Membrane Permeability Cell Survival Cell Biochemistry Structure-Activity Relationship Drug Discovery inhibitors medicine Structure–activity relationship Humans General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Pharmacology biology epigenetics Dose-Response Relationship Drug Molecular Structure Organic Chemistry cell permeability Esters In vitro Communications Histone medicine.anatomical_structure jmjc histone demethylases Docking (molecular) 2-oxoglutarate (2OG) oxygenases biology.protein Hydroxyquinolines Molecular Medicine Demethylase structure–activity relationships Intracellular HeLa Cells |
| Zdroj: | ChemMedChem Chemmedchem |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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