Abstract

Seeking Potent Selective and Cell Penetrant KDM4-Subfamily Inhibitors

Julian Blagg, Deputy Director, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research

Increasing evidence suggests that the human JmjC histone demethylase KDM4 subfamily plays an important role in cancer initiation and progression. To build further confidence in the therapeutic potential of inhibiting their demethylase activity, there is a critical need for the discovery of potent, selective and cell-penetrant KDM4-subfamily JmjC-domain inhibitors; in particular, to study the importance of demethylase activity versus other chromatin localisation or scaffolding functions of full length KDM4 proteins. This talk will describe our structure-based design approach towards the identification of potent JmjC histone demethylase inhibitors based upon the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold which demonstrate potent and selective biochemical affinity for the KDM4- and KDM5-subfamily demethylases over the KDM2, KDM3 and KDM6 subfamilies and describe their cell-based activity profiles.