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.
Abstract:
The glioma-associated family of transcription factors (GLI) have emerged as a promising therapeutic target for a variety of human cancers. In particular, GLI1 plays a central role as a transcriptional regulator for multiple oncogenic signaling pathways, including the hedgehog (Hh) signaling pathway. We undertook a computational screening approach to identify small molecules that directly bind GLI1 for potential development as inhibitors of GLI-mediated transcription. Through these studies, we identified compound 1, which is an 8-hydroxyquinoline, as a high-affinity binder of GLI1. Compound 1 inhibits GLI1-mediated transcriptional activity in several Hh-dependent cellular models, including a primary model of murine medulloblastoma. We also performed a series of computational analyses to define more clearly the mechanism(s) through which 1 inhibits GLI1 function after binding. Our results strongly suggest that binding of 1 to GLI1 does not prevent GLI1/DNA binding nor disrupt the GLI1/DNA complex, but rather, it induces specific conformational changes in the overall complex that prevent proper GLI function. These results highlight the potential of this compound for further development as an anti-cancer agent that targets GLI1.
Insights
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.
More Related Videos
05:29A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
12:22A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput
Published on: September 22, 2019
