Proteopedia

5ls6

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Structure of Human Polycomb Repressive Complex 2 (PRC2) with inhibitorStructure of Human Polycomb Repressive Complex 2 (PRC2) with inhibitor

Structural highlights

5ls6 is a 16 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
NonStd Res:
Gene:EZH2, KMT6 (HUMAN), EED (HUMAN), SUZ12, CHET9, JJAZ1, KIAA0160 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EZH2_HUMAN] Weaver syndrome. The disease is caused by mutations affecting the gene represented in this entry. [SUZ12_HUMAN] A chromosomal aberration involving SUZ12 may be a cause of endometrial stromal tumors. Translocation t(7;17)(p15;q21) with JAZF1. The translocation generates the JAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1 and the C-terminus part of SUZ12. It is frequently found in all cases of endometrial stromal tumors, except in endometrial stromal sarcomas, where it is rarer.[1]

Function

[EZH2_HUMAN] Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Compared to EZH2-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. 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, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [SUZ12_HUMAN] Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. 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.[16] [17] [18] [19] [20] [21] [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.[22] [23] [24] [25] [26] [27] [28] [29] [30]

Publication Abstract from PubMed

Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 muM, cellular EC50 = 0.032 muM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.

Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas.,Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT, Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N, Chen S, Wilson JR, Gamblin SJ J Med Chem. 2016 Nov 10;59(21):9928-9941. Epub 2016 Oct 28. PMID:27739677[31]

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

See Also

References

  1. ↑ Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53. PMID:11371647 doi:http://dx.doi.org/10.1073/pnas.101132598
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ Epping MT, Wang L, Edel MJ, Carlee L, Hernandez M, Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005 Sep 23;122(6):835-47. PMID:16179254 doi:http://dx.doi.org/10.1016/j.cell.2005.07.003
  7. ↑ Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006 May 1;20(9):1123-36. Epub 2006 Apr 17. PMID:16618801 doi:http://dx.doi.org/10.1101/gad.381706
  8. ↑ 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
  9. ↑ Kim DH, Villeneuve LM, Morris KV, Rossi JJ. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat Struct Mol Biol. 2006 Sep;13(9):793-7. Epub 2006 Aug 27. PMID:16936726 doi:http://dx.doi.org/10.1038/nsmb1142
  10. ↑ Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev. 2007 Jan 1;21(1):49-54. PMID:17210787 doi:http://dx.doi.org/10.1101/gad.1499407
  11. ↑ Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007 Mar 1;21(5):525-30. PMID:17344414 doi:http://dx.doi.org/10.1101/gad.415507
  12. ↑ Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell. 2008 Nov 21;32(4):503-18. doi: 10.1016/j.molcel.2008.11.004. PMID:19026781 doi:http://dx.doi.org/10.1016/j.molcel.2008.11.004
  13. ↑ 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
  14. ↑ Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, Bagchi A, Simon JA, Huang H. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010 Nov;12(11):1108-14. doi: 10.1038/ncb2116. Epub 2010 Oct 10. PMID:20935635 doi:10.1038/ncb2116
  15. ↑ Lee JM, Lee JS, Kim H, Kim K, Park H, Kim JY, Lee SH, Kim IS, Kim J, Lee M, Chung CH, Seo SB, Yoon JB, Ko E, Noh DY, Kim KI, Kim KK, Baek SH. EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012 Nov 30;48(4):572-86. doi: 10.1016/j.molcel.2012.09.004. Epub 2012 , Oct 11. PMID:23063525 doi:http://dx.doi.org/10.1016/j.molcel.2012.09.004
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006 May 1;20(9):1123-36. Epub 2006 Apr 17. PMID:16618801 doi:http://dx.doi.org/10.1101/gad.381706
  20. ↑ Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007 Mar 1;21(5):525-30. PMID:17344414 doi:http://dx.doi.org/10.1101/gad.415507
  21. ↑ 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
  22. ↑ 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
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 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
  27. ↑ 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
  28. ↑ 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
  29. ↑ 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
  30. ↑ 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
  31. ↑ Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT, Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N, Chen S, Wilson JR, Gamblin SJ. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas. J Med Chem. 2016 Nov 10;59(21):9928-9941. Epub 2016 Oct 28. PMID:27739677 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01315

5ls6, resolution 3.47Å

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