Targeting EZH2 in haematological malignancies


Session type:

Patrick Trojer1
1Constellation Pharmaceuticals, Cambridge, USA


Lysine methyltransferases and demethylases were identified as transcriptional co-regulators functioning by either preserving particular chromatin methylation states or by controlling placement and removal of histone lysine methylation marks to promote dynamic changes in gene expression. The development of small molecule methyltransferase and demethylase inhibitors provides a novel approach to affect the regulation of transcription, and thus potentially allowing interference with aberrant transcriptional programs as observed, for instance, in cancer.

Enhancer of Zeste Homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase, is widely implicated in tumour progression. The presence of a recurrent mutation of single residues in the EZH2 catalytic domain in germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and follicular lymphoma suggests that these cancers might be dependent on altered EZH2 molecular function. Small molecule inhibitors of EZH2 have recently demonstrated efficacy in GCB-DLBCL models and thus provide a new therapeutic approach to treat human lymphomas, especially cases with activating EZH2 mutations.

Constellation has identified, characterised and optimised potent, selective, reversible, orally bioavailable EZH2 small molecule inhibitors. We find that pharmacological inhibition of EZH2 causes selective cell viability defects across a number of haematological disease models beyond GCB-DLBCL harbouring EZH2 mutations. Genome-wide mapping of EZH2 and H3K27me3 sites in the absence and presence of the compound revealed that the EZH2 inhibitor caused significant changes to the local chromatin modification landscape, however only a subset of these alterations translated into gene expression changes. Various biological contexts that depend on EZH2 catalytic activity will be discussed.