Reference Detail

Ref Type Journal Article
PMID (28135235)
Authors Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, Zhang M, Zhang J, Yu Z, Li L, Teng L, Chuai S, Zhang C, Zhao M, Chan H, Chen Z, Fang D, Fei Q, Feng L, Feng L, Gao Y, Ge H, Ge X, Li G, Lingel A, Lin Y, Liu Y, Luo F, Shi M, Wang L, Wang Z, Yu Y, Zeng J, Zeng C, Zhang L, Zhang Q, Zhou S, Oyang C, Atadja P, Li E
Title An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.
Journal Nature chemical biology
Vol 13
Issue 4
Date 2017 Apr
URL
Abstract Text Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
EED226 EED226 is a small molecule inhibitor of PRC2 via direct binding to the H3K27me3 pocket of EED, which leads to altered PRC2 targeted gene expression and thus, may result in inhibition of cell proliferation, blockade of tumor growth, and tumor regression (PMID: 28135235).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
F120L missense unknown EZH2 F120L lies within the DNMT1, DNMT3B, and DNMT3A-interacting regions of the Ezh2 protein (UniProt.org). F120L has been demonstrated to occur as a drug resistant mutation in the context of EZH2 Y111N (PMID: 28135235), but has not been biochemically characterized and therefore, its effect on Ezh2 protein function is unknown (PubMed, Sep 2018). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EZH2 Y646N diffuse large B-cell lymphoma sensitive EED226 Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line harboring EZH2 Y646N demonstrated sensitivity to EED226, resulting in inhibition of cell proliferation in culture (PMID: 28135235). 28135235
EZH2 Y646S diffuse large B-cell lymphoma sensitive EED226 Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line harboring EZH2 Y646S demonstrated sensitivity to EED226, resulting in inhibition of cell proliferation in culture (PMID: 28135235). 28135235
EZH2 F120L EZH2 Y111N diffuse large B-cell lymphoma sensitive EED226 Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cells co-expressing EZH2 F120L and EZH2 Y111N were sensitive to EED226, demonstrating inhibition of cell proliferation in culture (PMID: 28135235). 28135235
EZH2 Y646F diffuse large B-cell lymphoma sensitive EED226 Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line harboring EZH2 Y646F demonstrated sensitivity to EED226, resulting in inhibition of cell proliferation in culture (PMID: 28135235). 28135235
EZH2 F120L EZH2 Y111N diffuse large B-cell lymphoma resistant EI1 Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cells co-expressing EZH2 F120L and EZH2 Y111N were resistant to EI1 in culture, demonstrating no inhibition of cell proliferation (PMID: 28135235). 28135235
EZH2 F120L EZH2 Y111N Advanced Solid Tumor resistant Tazemetostat Preclinical - Cell culture Actionable In a preclinical study, a cancer cell line co-expressing EZH2 F120L and EZH2 Y111N was resistant to Tazemetostat (EPZ-6438) in culture, demonstrating no inhibition of cell proliferation (PMID: 28135235). 28135235
EZH2 Y641N diffuse large B-cell lymphoma sensitive EED226 Preclinical - Cell line xenograft Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line harboring EZH2 Y641N demonstrated sensitivity to EED226, resulting in inhibition of cell proliferation in culture and delayed tumor growth and tumor regression in a cell line xenograft model (PMID: 28135235). 28135235
EZH2 Y641N diffuse large B-cell lymphoma sensitive EED226 + EI1 Preclinical - Cell culture Actionable In a preclinical study, EED226 and EI1 synergistically inhibited cell proliferation in a diffuse large B-cell lymphoma cell line harboring EZH2 Y641N in culture (PMID: 28135235). 28135235