Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7.

Philip A Gerken,Anthony Tumber,Stephanie B Hatch,Fengling Li,Susanne Müller,Masoud Vedadi,Rebecca Konietzny,Shane A Chandler,Benedikt M Kessler,Yijia Zhang,Justin L P Benesch,Oleg Fedorov,Akane Kawamura,Clarence Yapp,Martin D Smith,Barbara Mair,Stephen Wolstenhulme ,P.e Brennan ,Sebastian M Nijman ,Tamás Szommer

doi:10.1002/anie.201706788

Abstract

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.

Highlights

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes
As a result, targeting the epigenetic pathways responsible for these chemical modifications may represent a pivotal approach to addressing disease at the transcription level.[2]
In order to realize the potential of epigenetics in drug discovery, a toolkit of chemical probes that selectively target individual epigenetic proteins and allow researchers to clearly identify their downstream effects is invaluable.[3]

Summary

Introduction

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. Most inhibitors of the JmjC KDMs are iron-chelating 2-OG competitors (Figure 1).[8,9,10,11,12,13,14] many of these molecules achieve high levels of in vitro potency, they are frequently limited by a lack of selectivity and activity in cells.

Results

Conclusion