EZH2

Lysine methyltransferases and demethylases have been identified as transcriptional co-regulators 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. Enhancer of Zeste Homolog 2 (EZH2) is an important histone lysine methyltransferase that functions cooperatively as part of a multi-subunit complex known as Polycomb Repressive Complex 2 (PRC2). EZH2 is responsible for methylating a single lysine residue (K27) on the histone H3 N-terminal region.

EZH2 is over-expressed in many solid tumors and hematologic malignancies, where expression levels strongly correlate with late stage disease and poor prognosis. EZH2 is also activated by mutation in some diffuse large B-cell and follicular lymphomas and in cutaneous melanoma. Further, functional data implicate EZH2 in tumor initiation and progression, stem cell self-renewal, migration, angiogenesis and proper function of activated Tregs.

Constellation has leveraged its product engine to identify tractable series of small molecule inhibitors of EZH2.

Human PRC2 crystal structure with CPI EZH2 inhibitor.

Human PRC2 crystal structure with CPI EZH2 inhibitor.

The co-crystal structure of a Constellation EZH2 inhibitor and PRC2 illustrates that the compound directly binds to the EZH2 catalytic pocket and partially overlaps with the SAM binding site. Constellation’s lead compounds inhibit PRC2 enzymatic activity at picomolar concentrations and reduce global H3K27me3 levels at low nanomolar concentrations in a reversible manner. In disease-relevant B-cell lymphoma cell lines, Constellation’s EZH2 inhibitors alter PRC2 target gene expression and cause dose- and time-dependent cell killing. EZH2 inhibitor-induced apoptosis is observed in cell models representative of multiple non-Hodgkin lymphoma subtypes.

CPI-1205 is Constellation’s clinical stage EZH2 inhibitor. CPI-1205 caused complete regression in Diffuse Large B-cell Lymphoma xenograft models. The compound was well-tolerated in toxicology studies in rats and dogs. Human dose projections suggest oral, twice daily dosing schedule to achieve comprehensive target coverage.

Inhibition of PRC2 by CPI-1205 results in reactivation of PRC2 target genes, reduces global histone H3 lysine 27 trimethylation levels and shows impressive tumor growth inhibition in a lymphoma xenograft mouse model.

Inhibition of PRC2 by CPI-1205 results in reactivation of PRC2 target genes, reduces global histone H3 lysine 27 trimethylation levels and shows impressive tumor growth inhibition in a lymphoma xenograft mouse model.