期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00249
关键词
GLI1 negative modulators; quinoline; Hedgehog pathway; anticancer agents; pharmacophoric model; virtual screening
In this study, a virtual screening approach based on a five-feature pharmacophoric model was used to screen a database of commercially available compounds. The resulting quinoline derivatives showed significant reduction in GLI1 protein level and demonstrated submicromolar antiproliferative activity against human melanoma and medulloblastoma cell lines. Further structural modifications to the quinoline ring and chemical rigidification to an oxazino-quinoline scaffold provided insights for future ligand optimization.
A virtual screening approach based on a five-feature pharmacophoric model for negative modulators of GLI1 was applied to databases of commercially available compounds. The resulting quinoline derivatives showed significant ability to reduce the GLI1 protein level and were characterized by submicromolar antiproliferative activity toward human melanoma A375 and medulloblastoma DAOY cell lines. Decoration of the quinoline ring and chemical rigidification to an oxazino-quinoline scaffold allowed us to deduce SAR considerations for future ligand optimization.
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