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Review
. 2021 Oct 21;13(1):39-53.
doi: 10.1039/d1md00274k. eCollection 2022 Jan 27.

An overview of the development of EED inhibitors to disable the PRC2 function

Kai-Lu Liu  1 , Kongkai Zhu  1 , Hua Zhang  1
Affiliations
Review

An overview of the development of EED inhibitors to disable the PRC2 function

Kai-Lu Liu et al. RSC Med Chem. .

Abstract

Polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 lysine 27 (H3K27) and the enrichment of its catalytic product H3K27me3 is responsible for the silencing of tumor suppressor genes and the blocking of transcripts related to immunity and cell terminal differentiation. Aberrations of PRC2 components, such as mutation and overexpression, have been observed in various cancers, which makes PRC2 a potential therapeutic target for cancer. Up to now, targeting the enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represents the main strategy in the development of PRC2 inhibitors. Although significant progress has been made, new problems also emerge, e.g. the drug resistance caused by secondary mutations. In recent years, more and more efforts have shifted to another new strategy - targeting embryonic ectoderm development (EED) to disrupt its major interactions with other components, which are necessary to the PRC2 function, and some promising results have been obtained. This review summarizes the recent development of EED inhibitors as possible chemotherapy for cancer treatment, which could help accelerate future related research work.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Structures of representative EZH2 inhibitors. CPI-1205 and PF-06821497 are in the clinical trial stage, while EPZ-6438 (tazemetostat) has been approved by the U.S. FDA.
Fig. 2
Fig. 2. Two pockets in EED. The smaller top pocket is referred to as the “aromatic cage”, also known as the “Me3 pocket” with three sides formed from three aromatic residues F97, Y148 and Y365. The bottom pocket is mostly lined with hydrophobic residues that recognize and interact with the N-terminal α helix of EZH2.
Fig. 3
Fig. 3. The optimization process of EED162 to EED226. Firstly, the benzylhydropyridine ring on C-7 and C-8 of EED162 was removed to afford compound 1 with improved ligand efficiency (LE) and lipophilic efficiency (LipE). Secondly, under the assumption that the substitution of an aryl group at the C-8 position can obtain edge-to-face interactions, compound 2 with phenyl substitution at C-8 was synthesized. Thirdly, the ensuing scaffold hopping – replacing the cyano group with nitrogen – was performed, and compound 3 was then obtained. Finally, in the optimization of pharmacokinetic potency, EED226 with methylsulfonyl substitution was selected because of its low clearance, moderate half-life and high oral bioavailability.
Fig. 4
Fig. 4. Structures of EED162, EED210, EED396, EED666 and EED709, together with their IC50 values in an EED-H3K27me3 AlphaScreen competition binding assay. The red parts in the structures interact with the R367 side chain by penetrating into the deep pocket, while the central rings are located among F97, Y148 and Y365, and the blue parts are at the edge of the pocket and still interact with EED.
Fig. 5
Fig. 5. Structures of five aminoimidazole compounds (11–15) and the optimization process. (1) Replacing the methoxy group with an oxygen-containing ring; (2) optimizing the amine group in the piperidine ring; (3) combining (1) and (2); (4) substituting the guanidinium group with 2-aminoimidazolyl to improve permeability; (5) introducing an aliphatic group; (6) mitigating the potential liabilities of the phenyl ring. IC50 values represent the capability to inhibit the PRC2 activity; ELISA IC50 values represent the capability to inhibit the H3K27 methylation in G401 cells. N.D.: not determined.
Fig. 6
Fig. 6. Structures of a number of highly efficacious EED inhibitors.
Fig. 7
Fig. 7. The optimization process of compound 26 to EEDi-5285 and EEDi-1056. First, by introducing an ethoxycarbonyl group into 26, compound 27 with enhanced π–π stacking interactions with EED was obtained. To improve cation–π interactions, the replacement of the furan moiety with another aromatic ring was then performed, and compound 28 exhibiting high affinity for EED (IC50 = 18 nM) and good inhibition against Karpas422 cells (IC50 = 0.012 μM) was thus acquired. Next, compound 29 was generated by displacing the ethoxycarbonyl unit in 28 with a methylsulfonyl group. Ultimately, considering the improvement of the solubility, the replacement of the phenyl group in 29 with 2-cyclopropyl-5-pyridinyl and 2,6-dimethyl-3-pyridinyl was conducted to yield EEDi-5285 and EEDi-1056, respectively.
Fig. 8
Fig. 8. Structures of six initially identified EED-EZH2 inhibitors. In the FP experiment, apomorphine hydrochloride exhibited the best activity with an IC50 value of 15.50 μM. Both compounds 31 (IC50 = 54.90 μM) and 30 (IC50 = 63.88 μM) showed better activities than astemizole (IC50 = 93.80 μM).
Fig. 9
Fig. 9. Structures of several EZH2 and EED PROTACs.
None
Kailu Liu
None
Kongkai Zhu
None
Hua Zhang
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References

    1. Feinberg A. P. Koldobskiy M. A. Gondor A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 2016;17:284–299. doi: 10.1038/nrg.2016.13. - DOI - PMC - PubMed
    1. Skvortsova K. Iovino N. Bogdanovic O. Functions and mechanisms of epigenetic inheritance in animals. Nat. Rev. Mol. Cell Biol. 2018;19:774–790. doi: 10.1038/s41580-018-0074-2. - DOI - PubMed
    1. Chammas P. Mocavini I. Di Croce L. Engaging chromatin: PRC2 structure meets function. Br. J. Cancer. 2020;122:315–328. doi: 10.1038/s41416-019-0615-2. - DOI - PMC - PubMed
    1. Lavarone E. Barbieri C. M. Pasini D. Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat. Commun. 2019;10:1679. doi: 10.1038/s41467-019-09624-w. - DOI - PMC - PubMed
    1. Hojfeldt J. W. Laugesen A. Willumsen B. M. Damhofer H. Hedehus L. Tvardovskiy A. et al., Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. Nat. Struct. Mol. Biol. 2018;25:225–232. doi: 10.1038/s41594-018-0036-6. - DOI - PMC - PubMed