Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor.

Katherine S England,Paul E Brennan,Nicola A Burgess-Brown,Aleksandra Szykowska,Frank Von Delft,Giuseppe Scozzafava,Tobias Krojer,Akane Kawamura,Kahing Che,Anthony Tumber,Stanley S Ng,Michelle Daniel,Christopher J Schofield

doi:10.1039/c4md00291a

Abstract

A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity.

Highlights

The dynamic methylation of histone lysine residues is an important process in transcriptional regulation
The introduction of N3-methyl lysine methylation marks is catalysed by histone methyl transferases and their removal is catalysed by histone lysine demethylases (KDMs)
In order to nd selective inhibitors of JmjC KDMs, a new scaffold was designed based on the 2,20-bipyridine series wherein one of the pyridine rings was replaced with a triazole ring to give a different potential iron binding motif

Summary

Introduction

The dynamic methylation of histone lysine residues is an important process in transcriptional regulation. We report the development of a highly selective and potent inhibitor of the JmjC KDM KDM2A.

Results

Conclusion