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

Fabrizio Manetti; Barbara Stecca; Roberta Santini; Luisa Maresca; Giuseppe Giannini; Maurizio Taddei; Elena Petricci

doi:10.1021/acsmedchemlett.9b00639

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. eCollection 2020 May 14.

Authors

Fabrizio Manetti^{1

2}, Barbara Stecca³, Roberta Santini³, Luisa Maresca³, Giuseppe Giannini⁴, Maurizio Taddei^{1

2}, Elena Petricci¹

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.

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.