SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Curtin, Michael L.; Pliushchev, Marina; Li, Huan‐Qiu; Torrent, Maricel; Dietrich, Justin; Jakob, C.G.; Zhu, Haizhong; Zhao, Hongyu; Wang, Ying; Ji, Zhiqin; Clark, Richard F.; Sarris, Kathy; Selvaraju, Sujatha; Shaw, Bailin; Algire, Mikkel A.; He, Yiping; Richardson, Paul L.; Sweis, Ramzi F.; Sun, Chaohong; Chiang, Gary G.; Michaelides, Michel

doi:10.1016/j.bmcl.2017.02.030

Cited by 28 publications

(30 citation statements)

References 16 publications

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“…OICR-9429 binds WDR5 with an affinity of 50 nM as measured by isothermal titration calorimetry, inhibits the co-immunoprecipitation of an MLL peptide with WDR5 with an IC50 of 223 nM, and elicits a clear phenotypic response in cellular assays at 5 μM 24 . A-395, a potent and novel protein-protein interaction inhibitor that binds EED to inhibit the PRC2 complex, was initially identified via a high-throughput, small molecule screen utilizing a thermal shift assay (TSA) with EED protein, and subsequently optimized by incorporating a strategic sp 3 -rich ring constraint and appending polar functionalities to increase potency while decreasing cLogP 25,94 . EED26, another EED-targeting chemical probe, was discovered via a high-throughput campaign to find compounds inhibiting the catalytic activity of the reconstituted PRC2 complex 26 .…”

Section: Pharmacologically Targeting Wdr Domainsmentioning

confidence: 99%

“…Similarly, the geometry of the EED inhibitor-binding site is regulated by the conformation of W364, Y365 and R367. While the pocket is shallow in the apo and histone-bound states, conformational rearrangement of Y365 and adjacent residues (engaged either directly or indirectly in aromatic cage formation) produces a larger, deeper cavity that can accommodate small-molecule inhibitors (Fig 5d–f) 25,26,94–96 .…”

Section: Pharmacologically Targeting Wdr Domainsmentioning

confidence: 99%

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WD40 repeat domain proteins: a novel target class?

Schapira

Tyers

Torrent

et al. 2017

Nat Rev Drug Discov

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248

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Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. However, successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets as opposed to the much more common large, flat protein interaction surfaces. Here we review one of the most abundant PPI domains in the human proteome, the WD40 repeat domain (WDR), which has a central peptide-binding pocket. Recently, two WDR proteins, WDR5 and EED, have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDRs represent a novel target class for drug discovery? While clinical validation remains to be seen, a cautious optimism is justified, considering the ubiquitous involvement of WDR proteins across multiple disease-associated pathways. The druggability and structural diversity of WDR binding pockets suggest that this prevalent domain class could open-up areas of biology that have so far resisted drug discovery efforts.

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Section: Pharmacologically Targeting Wdr Domainsmentioning

confidence: 99%

Section: Pharmacologically Targeting Wdr Domainsmentioning

confidence: 99%

WD40 repeat domain proteins: a novel target class?

Schapira

Tyers

Torrent

et al. 2017

Nat Rev Drug Discov

Self Cite

248

221

View full text Add to dashboard Cite

show abstract

“…37,65 Although it is tempting to speculate that EED-mediated recognition of repressive histone marks could serve as a mechanism for recruitment of PRC2 to silenced loci, a large body of evidence has shown that stimulation of PRC2 catalytic activity and its recruitment on chromatin are completely uncoupled. 64,[66][67][68][69][70][71] Rather, this mechanism accounts for a positive-feedback loop: upon PRC2 deposition of the H3K27me3 mark through its basal level of activity, methylation of the neighbouring nucleosome is favoured, resulting in spreading of the histone mark along the linear chromatin fibre as well as along the regions that are in spatial proximity. 72 In addition to this, PRC2 is also able to self-stimulate via trimethylation of JARID2 at lysine 116 (JARID2K116me3) (Fig.…”

Section: Dna and Nucleosomesmentioning

confidence: 99%

Engaging chromatin: PRC2 structure meets function

2019

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Polycomb repressive complex 2 (PRC2) is a key epigenetic multiprotein complex involved in the regulation of gene expression in metazoans. PRC2 is formed by a tetrameric core that endows the complex with histone methyltransferase activity, allowing it to mono-, di-and tri-methylate histone H3 on lysine 27 (H3K27me1/2/3); H3K27me3 is a hallmark of facultative heterochromatin. The core complex of PRC2 is bound by several associated factors that are responsible for modulating its targeting specificity and enzymatic activity. Depletion and/or mutation of the subunits of this complex can result in severe developmental defects, or even lethality. Furthermore, mutations of these proteins in somatic cells can be drivers of tumorigenesis, by altering the transcriptional regulation of key tumour suppressors or oncogenes. In this review, we present the latest results from structural studies that have characterised PRC2 composition and function. We compare this information with data and literature for both gain-of function and loss-of-function missense mutations in cancers to provide an overview of the impact of these mutations on PRC2 activity.

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“…Therefore, the requirement for new types of EZH2 inhibitors is foreseeable. For example, new inhibitors targeting the cage of EED have been developed to abrogate the EED-H3K27me3 interaction and thereby prevent the initiation of H3K27me3-potentiated positive feedback activation of PRC2 [57][58][59][60][61] .…”

Section: Introductionmentioning

confidence: 99%

Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin

Lee¹,

Yu²,

Kumar

et al. 2017

Preprint

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SUMMARYPRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here, we report a step-wise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifest little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we further demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2 Y646X oncogenic mutations. These results revealed critical implications to the regulation and biology of PRC2 and a novel vulnerability in tackling PRC2-addicted cancers.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Cited by 28 publications

References 16 publications

WD40 repeat domain proteins: a novel target class?

WD40 repeat domain proteins: a novel target class?

Engaging chromatin: PRC2 structure meets function

Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin

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