EZH2

Official Full Name

enhancer of zeste 2 polycomb repressive complex 2 subunit

Organism

Homo sapiens

GeneID

2146

Background

This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

Synonyms

WVS; ENX1; KMT6; WVS2; ENX-1; EZH2b; KMT6A;

Protein Sequence

MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEWKQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNFMVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQYNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEELKEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHPFHATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPNNSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKMKPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPAPAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQNFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVSCKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDKYMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGEELFFDYRYSQADALKYVGIEREMEIP

Open

Approved Drug

1 +

Clinical Trial Drug

8 +

Discontinued Drug

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Detailed Information

EZH2(enhancer of zeste homolog 2) is a human homolog of the Zeste gene enhancer of Drosophila, located on human chromosome 7q35, containing 20 exons and 19 introns, encoding a protein molecule consisting of 746 amino acid residues. There is a WD repeat domain at the N-terminus that is involved in the targeting of EED and SUZ12; the C-terminus contains a SET domain associated with histone methyltransferase activity.

The polycomb group (PcG) is a group of apparent regulators that inhibit the transcription of target genes by modifying chromatin, which is highly conserved from fruit flies to mammals. PRC2 (polycomb repressive complex 2) is a complex of multi-subunit proteins consisting of EZH1(enhancer of zeste homologue 1, KMT6B) or EZH2(enhancer of zeste homologue 2, KMT6A), SUZ12(suppressor of zeste 12), and EED(embyronic ectoderm development). Among them, EZH1 /2 is a catalytic subunit of the PRC2 complex and has methyltransferase activity that catalyzes the trimethylation of histone H3 at position 27 or 9 and is an important transcriptional inhibitor. It is also involved in chromatin structure changes, gene expression, and growth regulation.

EZH2 Figure 1. Three ways of EZH2 action. (Burmeister, et al. 2016)

Burmeister summarized three modes of action of EZH2: (1) methylation of lysine 27 in histone 3(H3K27) as a "classical" effect of transcriptional repressors; only acting on the core component of the PRC2 complex. (2) Transcriptional activation of non-histone by lysine methylation. (3) JAK3 converts EZH2 to phosphorylation of transcriptional activators.

EZH2 and Heart Development

In cardiac development, EZH2 silences the expression of cardiac transcription factors through epigenetic modification and plays an important role in regulating the differentiation of early embryonic stem cells into cardiac cell lines and the expression of cardiac genes. And it participates in the maintenance of infant heart homeostasis. Studies have shown that EZH2 interacts with PcG family and some members of the non-PcG family (including long-chain non-coding RNA ( lncRNA) and microRNA) in cardiac development and cardiomyocyte differentiation. It has been determined that more than 50 genes are coordinated by EZH2 and PcG family members during heart development, including Isl1, Tbx2, Tbx3, AND1, Irx5 (Iroquois homeobox 5) and Six1. Other studies have found that Hey2 is a downstream target gene of EZH2, which plays an important role in cardiac myocyte proliferation and cardiac morphogenesis, and that EZH2 regulates Hey2 independently of Notch signaling activity. Correspondingly, embryos that knock out EZH1 develop normally but affect myocardial regeneration and cardiac function in postnatal myocardial infarction.

EZH2 not only participates in the methylation modification of histones, but also regulates the methylation modification of non-histones. For example, EZH2 can methylate the 299th lysine of the cardiac transcription factor GATA4, thereby inhibiting its transcription. As a key dose-dependent transcriptional regulator in human and mouse fetal heart development, GATA4 recruits p300 to specific chromatin sites, while p300 acetylated GATA4 activates GATA4 transcriptional activity. In the fetal heart, EZH2 inhibits the recruitment of p300 by GATA4 by methylation of the 379th lysine of GATA4, thereby inhibiting the transcriptional activity and gene expression of GATA4. However, excessive inhibition hinders the differentiation of embryonic stem cells into cardiomyocytes, resulting in incomplete cardiac development. Conversely, excessive transcription of GATA4 causes cardiac hypertrophy, so EZH2 directly inhibits abnormal transcription of GATA4 and prevents hyperplasia of the myocardium.

EZH2 Inhibitor

Compound 24 (UNC1999) is a chemical tool reported by Knoze et al. for EZH2 and EZH1 studies, showing better EZH2 in vitro activity (IC50 < 10 nmol·L^-1) and lipophilicity over compounds 20 and 21 ( clogP = 3. 1). Mechanism of action studies showed that compound 24 competes with the binding region of SAM in EZH2 [Ki = (4.6 ± 0.8) nmol·L^-1].Ansari et al. designed a series of compounds containing dihydroanthracene and pyridone structures, of which compound 29 has a good EZH2 inhibitory activity IC50 of 29 nmol·L^-1. It is highly selective for EZH2 and is 200 times more active than EZH1. In vitro pharmacokinetic studies showed that Compound 29 had better solubility and human and rat liver microsomal clearance compared to Compound 26.

In 2015, Campbell et al. reported another highly effective and orally effective EZH2 inhibitor 33 (EPZ011989) with a Ki value of less than 3 nmol·L ^-1 compared to the EZH2 enzyme. Due to its good in vivo and in vitro activity and PK/PD properties, it is currently in preclinical studies. Based on compound 26, Song et al. designed a highly efficient, highly selective and efficacious small molecule EZH2 inhibitor 34 (ZLD1039) with IC50 values of (5.6±0.36) nmol·L^-1 and (15±0.51) nmol·L^-1 for wild-type and mutant EZH2, respectively. It activates the silencing anti-cancer gene of H3K27me3, arrests the cell division cycle and induces apoptosis. In the mouse KAPPAS-422B cell lymphoma xenograft model, Compound 34 significantly inhibited the growth of B-cell lymphoma and is currently undergoing preclinical studies.

In recent years, reports on various lysine methyltransferase inhibitors have been increasing, and many target inhibitors are currently immature or have a single structure. For example, the activity of the EZH2 inhibitor is mainly a compound containing a pyridone structure and mainly acts on the mutant EZH2. The independent enzyme structure of EZH2 has not been reported, which limits the development of EZH2 inhibitors. DOT1L inhibitors are highly selective because they do not contain the SET domain, but the structure is primarily SAM analog. The new structure of DOT1L inhibitors is one of the hot spots of current research.

References:

Burmeister, T. (2016). Ezh2: a pleiotropic protein. Blood, 128(7), 888.
Konze, K. D., Ma, A., Li, F., Barsyte-Lovejoy, D., Parton, T., & Macnevin, C. J., et al. (2013). An orally bioavailable chemical probe of the lysine methyltransferases ezh2 and ezh1. Acs Chemical Biology, 8(6), 1324.
Ansari, A., Satalkar, S., Patil, V., Shete, A. S., Kaur, S., & Gupta, A., et al. (2016). Novel 3-methylindoline inhibitors of ezh2: design, synthesis and sar. Bioorganic & Medicinal Chemistry Letters, 27(2).
Campbell, J. E., Kuntz, K. W., Knutson, S. K., Warholic, N. M., Keilhack, H., & Wigle, T. J., et al. (2015). Epz011989, a potent, orally-available ezh2 inhibitor with robust in vivo activity. Acs Medicinal Chemistry Letters, 6(5), 491-495.
Song, X., Gao, T., Wang, N., Feng, Q., You, X., & Ye, T., et al. (2016). Selective inhibition of ezh2 by zld1039 blocks h3k27methylation and leads to potent anti-tumor activity in breast cancer. Sci Rep, 6, 20864.
Gao, T., Zhang, L., Zhu, Y., Song, X., Feng, Q., & Lei, Q., et al. (2016). Zld1122, a novel ezh2 and ezh1 small molecular inhibitor, blocks h3k27 methylation and diffuse large b cell lymphoma cell growth. Rsc Advances, 6(34), 28512-28521.

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