Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

Lingel, Andreas; Sendzik, Martin; Huang, Ying; Shultz, Michael D.; Cantwell, John; Dillon, Michael P.; Fu, Xingnian; Fuller, John; Gabriel, Tobias; Gu, Justin; Jiang, Xiangqing; Li, Ling; Liang, Fang; McKenna, Maureen; Qi, Wei; Rao, Weijun; Sheng, Xijun; Shu, Wei; Sutton, James; Taft, Benjamin R.; Wang, Long; Zeng, Jianhuang; Zhang, Hailong; Zhang, Maya; Zhao, Kehao; Lindvall, Mika K.; Bussiere, Dirksen E.

doi:10.1021/acs.jmedchem.6b01473

Cited by 53 publications

(51 citation statements)

References 33 publications

(78 reference statements)

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“…In an effort to improve selectivity of ritanserin for DGKα, we explored ligand deconstruction (Hajduk et al, 2000; Kozakov et al, 2015; Lingel et al, 2017) strategies to evaluate the contributions of representative fragments for binding affinity and selectivity. We hypothesized that the 4-substituted piperidine moiety of ritanserin (highlighted in red, Figure 7C) is a likely pharmacophore required for DGKα inhibition because of conservation of this motif across several DGKα inhibitors (Boroda et al, 2017) (Figure S3E).…”

Section: Resultsmentioning

confidence: 99%

The Ligand Binding Landscape of Diacylglycerol Kinases

Franks

Campbell

Purow

et al. 2017

Cell Chemical Biology

109

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SUMMARY Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP- and small molecule-binding motifs of representative members from all five DGK subtypes. We use chemical proteomics to discover an unusual binding mode for the DGK-alpha (DGKα) inhibitor ritanserin, including interactions at the atypical C1 domain distinct from the ATP binding region. Unexpectedly, deconstruction of ritanserin yielded a fragment compound that blocks DGKα activity through a conserved binding mode and enhanced selectivity against the kinome. Collectively, our studies illustrate the power of chemical proteomics to profile protein-small molecule interactions of lipid kinases for fragment-based lead discovery.

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Section: Resultsmentioning

confidence: 99%

The Ligand Binding Landscape of Diacylglycerol Kinases

Franks

Campbell

Purow

et al. 2017

Cell Chemical Biology

109

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“…During early development of porcine embryos, DNA methylation decreases to a minimum after ZGA at the 8-cell stage, and is re-established in blastocysts. [31][32][33] We observed that EZH2 showed significant high expression in the 8-cell embryo and SUZ12 was remarkably high in the morula and EB ( Figure 6C). H3K4me3 is related to activation of gene transcription, 30,31 and the regulators SETD1A and SETD1B were remarkably high in the 8-cell embryo when ZGA occured, and then the expressions decreased in EB ( Figure 6B).…”

Section: Expression Dynamics Of Epigenetic Regulators During the Emmentioning

confidence: 86%

Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Kong

Zhang

et al. 2019

FASEB j.

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The inner cell mass (ICM) in blastocyst is the origin of all somatic and germ cells in mammals and pluripotent stem cells (PSCs) in vitro. As the conserved principles between pig and human, here we performed comprehensive single‐cell RNA‐seq for porcine early embryos from oocyte to early blastocyst (EB). We show the specification of the ICM and trophectoderm in morula and the molecular signature of the precursors. We demonstrate the existence of naïve pluripotency signature in morula and ICM of EB, and the specific pluripotent genes and the activity of signalling pathways highlight the characteristics of the naïve pluripotency. We observe the absence of dosage compensation with respect to X‐chromosome (XC) in morula, and incomplete dosage compensation in the EB. However, the dynamics of dosage compensation may be independent of the expression of XIST induced XC inactivation. Our study describes molecular landmarks of embryogenesis in pig that will provide a better strategy for derivation of porcine PSCs and improve research in regenerative medicine.

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“…Collectively, this information has been very helpful for guiding the lead optimization effort. The manuscripts for the optimization results for EED210 and EED162 will be published separately [24, 39, 40]. In conclusion, we have discovered a new class of PRC2 allosteric inhibitors through binding to EED.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED

Zhang

et al. 2017

PLoS ONE

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Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays a key role in gene regulation and is a known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED is the regulatory subunit of PRC2. It binds to the tri-methylated lysine 27 of the histone H3 (H3K27me3), and through which stimulates the activity of PRC2 allosterically. Recently, we disclosed a novel PRC2 inhibitor EED226 which binds to the K27me3-pocket on EED and showed strong antitumor activity in xenograft mice model. Here, we further report the identification and validation of four other EED binders along with EED162, the parental compound of EED226. The crystal structures for all these five compounds in complex with EED revealed a common deep pocket induced by the binding of this diverse set of compounds. This pocket was created after significant conformational rearrangement of the aromatic cage residues (Y365, Y148 and F97) in the H3K27me3 binding pocket of EED, the width of which was delineated by the side chains of these rearranged residues. In addition, all five compounds interact with the Arg367 at the bottom of the pocket. Each compound also displays unique features in its interaction with EED, suggesting the dynamics of the H3K27me3 pocket in accommodating the binding of different compounds. Our results provide structural insights for rational design of novel EED binder for the inhibition of PRC2 complex activity.

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Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

Cited by 53 publications

References 33 publications

The Ligand Binding Landscape of Diacylglycerol Kinases

The Ligand Binding Landscape of Diacylglycerol Kinases

Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig

Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED

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