2. Academic Validation
  3. Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

  • EMBO J. 2015 Jan 13;34(2):200-17. doi: 10.15252/embj.201489213.
Paola Infante 1,  Mattia Mori 1,  Romina Alfonsi 2,  Francesca Ghirga 3,  Federica Aiello 4,  Sara Toscano 1,  Cinzia Ingallina 1,  Mariangela Siler 2,  Danilo Cucchi 2,  Agnese Po 2,  Evelina Miele 1,  Davide D'Amico 2,  Gianluca Canettieri 2,  Enrico De Smaele 5,  Elisabetta Ferretti 5,  Isabella Screpanti 2,  Gloria Uccello Barretta 4,  Maurizio Botta 6,  Bruno Botta 7,  Alberto Gulino 8,  Lucia Di Marcotullio 9
Affiliations

Affiliations

  • 1 Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
  • 2 Department of Molecular Medicine, University La Sapienza, Rome, Italy.
  • 3 Dipartimento di Chimica e Tecnologie del Farmaco, University La Sapienza, Rome, Italy.
  • 4 Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy.
  • 5 Department of Experimental Medicine, University La Sapienza, Rome, Italy.
  • 6 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA.
  • 7 Dipartimento di Chimica e Tecnologie del Farmaco, University La Sapienza, Rome, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
  • 8 Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy Department of Molecular Medicine, University La Sapienza, Rome, Italy Istituto Pasteur, Fondazione Cenci-Bolognetti - University La Sapienza, Rome, Italy IRCCS Neuromed, Pozzilli, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
  • 9 Department of Molecular Medicine, University La Sapienza, Rome, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
PMID: 25476449 DOI: 10.15252/embj.201489213
Abstract

Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or Other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling.

Keywords

Gli inhibitors; Gli1–DNA interaction; Hedgehog; cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122590
    98.05%, Gli1-DNA Interaction Inhibitor
    Gli