Application of PF-06821497 as a EZH2 Inhibitor

PF-06821497 is a potent EZH2 Inhibitor which can be used for the treatment of relapsed/refractory SCLC (small cell lung cancer), castration resistant prostate cancer, and follicular lymphoma. The structure of PF-06821497 is showed in figure 1.

EZH2 (Enhancer of zeste homolog 2) is one of the three core subunits of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that participates in histone methylation and, ultimately, transcriptional repression.

Fig. 1 Structure of PF-06821497

Application as a EZH2 Inhibitor

EZH2 plays critical roles in a range of biological processes including organ development and homeostasis, epigenomic and transcriptomic regulation, gene repression and imprinting, and DNA damage repair. However, when mutation happens or expression is abnormal (including overexpression, downregulated expression, and expression loss), it is related to cancer initiation, progression, and metastasis.

• EZH2 and Cancer

EZH2 contains a SET domain and functions as a histone methyltransferase and it is involved in methylation of lysine 27 on histone H3, which is then transformed to H3K27me3, leading to heterochromatin formation and priming for epigenetic gene silencing and transcriptional repression (see figure 2)[1].

Fig. 2 Regulation of EZH2 in tumor cells and immune cells

Hyperactivation of EZH2 is found in a variety of malignancies including prostate, breast, uterine, gastric, and renal cell cancers in addition to melanoma. And EZH2 expression is correlated with aggressiveness, metastasis, and poor prognosis in most of these cancers. The extensive reports describing EZH2 hyperactivation in various cancers is listed in table 1[2].

• PF-06821497 (the EZH2 inhibitor)

A growing area of interest within cancer treatment are the targeted epigenetic regulators. Epigenetic regulation is a genomic process that reversibly modifies gene expression without altering DNA sequencing. One way to regulate gene expression is through inhibition of enhancer of EZH2. Pei-Pei Kung[3] reported that PF-06821497 is a potent, selective, and orally active Enhancer of EZH2 inhibitor. Importantly, PF-06821497 displayed superior LipE among all analogs synthesized in the lactam series. This superior LipE enabled the combination of excellent potency, sufficient metabolic stability, permeability, and solubility properties.