5u69

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Polycomb protein EED in complex with inhibitor: (3R,4S)-1-[(2-methoxyphenyl)methyl]-N,N-dimethyl-4-(1-methylindol-3-yl)pyrrolidin-3-aminePolycomb protein EED in complex with inhibitor: (3R,4S)-1-[(2-methoxyphenyl)methyl]-N,N-dimethyl-4-(1-methylindol-3-yl)pyrrolidin-3-amine

Structural highlights

5u69 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.28Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EED_HUMAN Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Publication Abstract from PubMed

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.,Curtin ML, Pliushchev MA, Li HQ, Torrent M, Dietrich JD, Jakob CG, Zhu H, Zhao H, Wang Y, Ji Z, Clark RF, Sarris KA, Selvaraju S, Shaw B, Algire MA, He Y, Richardson PL, Sweis RF, Sun C, Chiang GG, Michaelides MR Bioorg Med Chem Lett. 2017 Apr 1;27(7):1576-1583. doi:, 10.1016/j.bmcl.2017.02.030. Epub 2017 Feb 20. PMID:28254486[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Sewalt RG, van der Vlag J, Gunster MJ, Hamer KM, den Blaauwen JL, Satijn DP, Hendrix T, van Driel R, Otte AP. Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Mol Cell Biol. 1998 Jun;18(6):3586-95. PMID:9584199
  2. ↑ van der Vlag J, Otte AP. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet. 1999 Dec;23(4):474-8. PMID:10581039 doi:10.1038/70602
  3. ↑ Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003 Oct 15;22(20):5323-35. PMID:14532106 doi:10.1093/emboj/cdg542
  4. ↑ Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004 Oct 13;23(20):4061-71. Epub 2004 Sep 23. PMID:15385962 doi:10.1038/sj.emboj.7600402
  5. ↑ Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, Farnham PJ. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004 Jul 1;18(13):1592-605. PMID:15231737 doi:10.1101/gad.1200204
  6. ↑ Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004 Jul 2;15(1):57-67. PMID:15225548 doi:10.1016/j.molcel.2004.06.020
  7. ↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
  8. ↑ Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol. 2008 Apr;28(8):2718-31. doi: 10.1128/MCB.02017-07. Epub 2008 Feb, 19. PMID:18285464 doi:10.1128/MCB.02017-07
  9. ↑ Xu C, Bian C, Yang W, Galka M, Ouyang H, Chen C, Qiu W, Liu H, Jones AE, Mackenzie F, Pan P, Li SS, Wang H, Min J. Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2). Proc Natl Acad Sci U S A. 2010 Oct 25. PMID:20974918 doi:10.1073/pnas.1008937107
  10. ↑ Curtin ML, Pliushchev MA, Li HQ, Torrent M, Dietrich JD, Jakob CG, Zhu H, Zhao H, Wang Y, Ji Z, Clark RF, Sarris KA, Selvaraju S, Shaw B, Algire MA, He Y, Richardson PL, Sweis RF, Sun C, Chiang GG, Michaelides MR. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. Bioorg Med Chem Lett. 2017 Apr 1;27(7):1576-1583. doi:, 10.1016/j.bmcl.2017.02.030. Epub 2017 Feb 20. PMID:28254486 doi:http://dx.doi.org/10.1016/j.bmcl.2017.02.030

5u69, resolution 1.28Å

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