EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity

Abstract

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

“…It is expected that tumor types in which EZH2 gain-offunction mutations occur (e.g., DLBCL and FL) (Campbell et al 2015) as well as tumors harboring mutations in SWI/SNF components (Wilson et al 2010;Knutson et al 2013;Bitler et al 2015) might benefit from these molecules. However, the long-term impact of such inhibition should be carefully examined in light of transcriptional instability and irreversible changes resulting from PRC2 disruption.…”

The roles of Polycomb group proteins in hematopoietic stem cells and hematological malignancies

“…These findings have sparked an increasing interest in PcG proteins as therapeutic targets in recent years. Actually, several research groups have discovered low molecular weight compounds that inhibit the enzymatic activity of Ezh2 and show a strong antitumor effect in cell lines and xenograft models of lymphoma with gain-of-function mutations in Ezh2 [90][91][92]. Another compound that was discovered is stabilized α-helix of EZH2 peptide (SAH-EZH2), which decreases the H3K27me3 level by inhibiting binding of Ezh2 and EED.…”

Discovery, design, and synthesis of indole-based EZH2 inhibitors

“…Searching for a stable saturated system, a series of piperidine analogs were synthesized (19 and 20). The N-methyl piperidine derivative (19) was biochemically potent and had very low microsomal metabolism, but performed poorly in our cellular assay. In contrast to piperidine 19, sulfonamide 20 showed excellent biochemical and cellular potency with an EC 50 of less than 100 nM.…”

“…Through these efforts a variety of small molecule inhibitors of EZH2 have been described which produce robust phenotypes both in vitro and in vivo ( Figure 1). [11][12][13][14][15][16][17][18][19] Figure 1. Reported EZH2 inhibitors.…”