Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity

Oncogene volume 28, pages 1477–1484 (2009)Cite this article

Abstract

Histone deacetylases (HDACs) play a key role in the regulation of gene expression and chromatin structure, and drugs targeting these enzymes might have an important impact in the treatment of human cancer. Herein, we report the characterization of (1H)-pyrroles as a new subfamily of HDAC inhibitors obtained by computational modeling of class-I human HDACs. From a functional standpoint, (1H)-pyrroles are powerful inductors of acetylation of histones H3 and H4, and restore the expression of growth-inhibitory genes. From a cellular view, these compounds cause a marked decrease in the viability of cancer cells in vitro and in vivo, associated with a cell-cycle arrest at G2/M and an inhibition of angiogenesis. Thus, (1H)-pyrroles emerge as a novel group of HDAC inhibitors with promising antitumoral features.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Balakin KV, Ivanenkov YA, Kiselyov AS, Tkachenko SE . (2007). Histone deacetylase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anticancer Agents Med Chem 7: 576–592.

    Article  CAS  Google Scholar 

  • Chiorazzi N, Rai KR, Ferrarini M . (2005). Chronic lymphocytic leukemia. N Engl J Med 352: 804–815.

    Article  CAS  Google Scholar 

  • Esteller M . (2007). Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298.

    Article  CAS  Google Scholar 

  • Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA et al. (1999). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401: 188–193.

    Article  CAS  Google Scholar 

  • Folkman J . (2007). Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273–286.

    Article  CAS  Google Scholar 

  • Jenuwein T, Allis CD . (2001). Translating the histone code. Science 293: 1074–1080.

    Article  CAS  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al. (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7: 437–443.

    Article  Google Scholar 

  • Kouzarides T . (2007). Chromatin modifications and their function. Cell 128: 693–705.

    Article  CAS  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ . (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 46: 3–26.

    Article  CAS  Google Scholar 

  • Maier T, Bar T, Beckers T, Zimmermann A, Dullweber F, Gekeler V . (2006). Sulfonylpyrroles as histone deacetylase inhibitors. WO/2006/105979.

  • Marks PA . (2007). Discovery and development of SAHA as an anticancer agent. Oncogene 26: 1351–1356.

    Article  CAS  Google Scholar 

  • Massa S, Mai A, Sbardella G, Esposito M, Ragno R, Loidl P et al. (2001). 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors. J Med Chem 44: 2069–2072.

    Article  CAS  Google Scholar 

  • Richardson B . (2007). Primer: epigenetics of autoimmunity. Nat Clin Pract Rheumatol 3: 521–527.

    Article  CAS  Google Scholar 

  • Sadri-Vakili G, Cha JH . (2006). Mechanisms of disease: histone modifications in Huntington's disease. Nat Clin Pract Neurol 2: 330–338.

    Article  CAS  Google Scholar 

  • Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ et al. (2004). Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12: 1325–1334.

    Article  CAS  Google Scholar 

  • Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D et al. (2004). Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 101: 15064–15069.

    Article  CAS  Google Scholar 

  • Villar-Garea A, Esteller M . (2004). Histone deacetylase inhibitors: understanding a new wave of anticancer reagents. Int J Cancer 112: 171–178.

    Article  CAS  Google Scholar 

  • Vivanco S, Lecea B, Arrieta A . (2000). Origins of the loss of concertedness in pericyclic reactions: theoretical prediction and direct observation of stepwise mechanisms in [3+2] thermal cycloadditions. J Am Chem Soc 122: 6078–6092.

    Article  CAS  Google Scholar 

  • Wang D-F, Wiest O, Helquist P, Lan-Hargest H-Y, Wiech NL . (2004). On the function of the 14 Å long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors. J Med Chem 47: 3409–3417.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants SAF2007-00027-65134, Consolider CSD2006-49, the Spanish Association Against Cancer (AECC), FP6 Grant SMARTER, Ikerchem Ltd., The Universidad del País Vasco-Euskal Herriko Unibertsitatea (Grant UE07/16), the Gobierno Vasco-Eusko Jaurlaritza (Grant 9/UPV00170.215-13548) and the Spanish Ministerio de Educación y Ciencia (CTQ2007-67528/BQU). SR is a ‘Ramon y Cajal’ Researcher. ME is an ICREA Research Professor.

Author information

Author notes

  1. A Zubia and S Ropero: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Chemistry-Quimica-Kimika Fakultatea, Universidad del Pais Vasco-Euskal Herriko Unibertsitatea, San Sebastian-Donostia, Euskadi, Spain

    A Zubia, D Otaegui & F P Cossío

  2. IkerChem SL, Avda. Tolosa, San Sebastian, Spain

    A Zubia

  3. Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, Spain

    S Ropero, E Ballestar, M F Fraga, M Boix-Chornet, M Berdasco & M Esteller

  4. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL) and Catalan Institute of Oncology (ICO), L’Hospitalet, Barcelona, Catalonia, Spain

    S Ropero, E Ballestar, M Berdasco & M Esteller

  5. Departamento Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Alcala, Alcala de Henares, Madrid, Spain

    S Ropero

  6. Department of Neuroanatomy and Cell Biology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    A Martinez

  7. Departament de Ciencies Fisiologiques II, IDIBELL-Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain

    L Coll-Mulet & J Gil

  8. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    M Esteller

Authors
  1. A Zubia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Ropero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Otaegui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Ballestar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M F Fraga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Boix-Chornet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Berdasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Coll-Mulet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Gil
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F P Cossío
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Esteller.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zubia, A., Ropero, S., Otaegui, D. et al. Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity. Oncogene 28, 1477–1484 (2009). https://doi.org/10.1038/onc.2008.501

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.501

Keywords

This article is cited by

Search

Advanced search

Quick links