Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor
Radha Charan Dash1, Jiachen Wen1, Angela M Zaino1
1Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
Researchers identified compound 1, an 8-hydroxyquinoline, as a GLI1 inhibitor. This compound targets GLI1-mediated transcription in cancer cells by inducing conformational changes, not by disrupting DNA binding, offering potential as an anti-cancer agent.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioma-associated oncogene homolog 1 (GLI1) is a key transcription factor regulating oncogenic pathways, including hedgehog (Hh) signaling.
- GLI1's central role in cancer makes it a promising therapeutic target.
Purpose of the Study:
- To identify small molecules that bind GLI1 and inhibit its transcriptional activity.
- To elucidate the mechanism of GLI1 inhibition by a novel compound.
Main Methods:
- Computational screening to identify GLI1 binders.
- In vitro assays to assess GLI1-mediated transcriptional activity.
- Computational analyses to determine the binding mechanism.
Main Results:
- Compound 1, an 8-hydroxyquinoline, was identified as a high-affinity GLI1 binder.
- Compound 1 inhibited GLI1 transcriptional activity in Hh-dependent cancer models, including medulloblastoma.
- Mechanism of action involves inducing conformational changes in GLI1, not preventing DNA binding.
Conclusions:
- Compound 1 is a potent inhibitor of GLI1 function.
- The novel mechanism of action suggests potential for developing GLI1-targeted anti-cancer therapies.
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