Manetti Fabrizio, Stecca Barbara, Santini Roberta, Maresca Luisa, Giannini Giuseppe, Taddei Maurizio, Petricci Elena
Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, via Aldo Moro 2, I-53100 Siena, Italy.
Lead Discovery Siena, via Fiorentina 1, I-53100 Siena, Italy.
ACS Med Chem Lett. 2020 Mar 25;11(5):832-838. doi: 10.1021/acsmedchemlett.9b00639. eCollection 2020 May 14.
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.
从已知的GLI1抑制剂出发，采用基于药效团的虚拟筛选方法对市售化合物数据库进行筛选，旨在鉴定新的GLI1调节剂。结果，出现了三种不同的化学骨架，其特点是具有显著降低小鼠NIH3T3细胞内源性Hedgehog-GLI信号通路的转录活性和GLI1蛋白水平的能力。它们在人黑色素瘤（A375）和髓母细胞瘤（DAOY）细胞系中还表现出微摩尔级的抗增殖活性，而对非肿瘤性乳腺上皮细胞无细胞毒性。
