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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.

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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.

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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

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  1. A Zubia
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  2. S Ropero
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  3. D Otaegui
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  9. L Coll-Mulet
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  12. M Esteller
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Corresponding author

Correspondence to M Esteller.

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

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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

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

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