Enhancer of zeste homolog 2 (EZH2) inhibitors

Abstract

Dysregulation of the histone methyltransferase EZH2 plays a critical role in the development of a variety of malignancies including B-cell lymphomas. As a result, a series of small molecule inhibitors of EZH2 have been developed and studied in the pre-clinical setting. Three EZH2 inhibitors: tazemetostat (EPZ-6438), GSK2816126 and CPI-1205 have moved into phase I/phase II clinical trials in patients with non-Hodgkin lymphoma and genetically defined solid tumors. Early data from the tazemetostat trials indicate an acceptable safety profile and early signs of activity in diffuse large B-cell lymphoma and follicular lymphoma, including patients with EZH2 wild-type and mutant tumors. In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.

Keywords: EZH2 inhibitors; Epigenetic; non-Hodgkin lymphoma.

Figure 1. Mechanism of EZH2 in normal and malignant B-cells:

(A) EZH2 forms the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The other core subunits in this complex include: embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and retinoblastoma (Rb) associated protein 46. EZH2 is responsible for methylating lysine 27 of histone 3 to generate H3K27me3, a histone mark associated with a more condensed chromatin and transcriptional gene repression. (B) When naïve B-cells are activated, they differentiate into antibody-secreting plasma cells or, alternatively, suspend the plasma cell program to enter the germinal center (GC) reaction. The transition to GC B-cells is characterized by increased expression of EZH2, which results in repression of genes that control plasma cell differentiation. Once GC B-cells complete affinity maturation, EZH2 levels decrease, enabling the expression of genes that control cell proliferation and mediate terminal differentiation, ultimately resulting in plasma cell formation. The occurrence of EZH2 somatic mutations aberrantly sustains repression of these proliferation checkpoint and differentiation genes, resulting in GC hyperplasia. Additional oncogenic hits, such as BCL2 or BCL6 translocations, enable transformation of GC B-cells to GCB-DLBCL or FL.

Figure 2. Schematic representation of mechanism of action of EZH2 inhibitors:

(A) The SET domain is the catalytic domain of the EZH2 methyltransferase. It catalyzes transfer of a methyl group from a universal methyl donor SAM (S-Adenosyl-L-methionine) methylating lysine 27 on Histone H3 (H3K27) associated with a more condensed chromatin and transcriptional gene repression. (B) The EZH2 inhibitors in clinical trials inhibit EZH2 through competitive inhibition with SAM causing de-repression of plasma cell transcription program and of checkpoint genes and eventually cell death.