Pharmacophore-Based Virtual Screening for Identification of Negative Modulators of GLI1 as Potential Anticancer Agents

  • ACS Med Chem Lett. 2020 Mar 25;11(5):832-838. doi: 10.1021/acsmedchemlett.9b00639.
Fabrizio Manetti  1  2 ,  Barbara Stecca  3 ,  Roberta Santini  3 ,  Luisa Maresca  3 ,  Giuseppe Giannini  4 ,  Maurizio Taddei  1  2 ,  Elena Petricci  1
Affiliations
  • 1. Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100 Siena, Italy.
  • 2. Lead Discovery Siena, via Fiorentina 1, I-53100 Siena, Italy.
  • 3. Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Viale Pieraccini 6, I-50139 Firenze, Italy.
  • 4. R&D, Alfasigma SpA, I-00071 Pomezia (Roma), Italy.
PMID: 32435392 DOI: 10.1021/acsmedchemlett.9b00639
Abstract

Starting from known GLI1 inhibitors, a pharmacophore-based virtual screening approach was applied to databases of commercially available compounds with the aim of identifying new GLI1 modulators. As a result, three different chemical scaffolds emerged that were characterized by a significant ability to reduce the transcriptional activity of the endogenous Hedgehog-GLI pathway and GLI1 protein level in murine NIH3T3 cells. They also showed a micromolar antiproliferative activity in human melanoma (A375) and medulloblastoma (DAOY) cell lines, without cytotoxicity in non-neoplastic mammary epithelial cells.