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. GLI1 is a transcription factor implicated as a therapeutic target for multiple forms of cancer. This work describes the identification and initial evaluation of a small molecule GLI1 inhibitor with promising anti-cancer properties. In addition, these studies probe the mechanism of action through which this compound inhibits GLI-mediated signaling.
Original language | English (US) |
---|---|
Pages (from-to) | 265-276 |
Number of pages | 12 |
Journal | Molecular Therapy Oncolytics |
Volume | 20 |
DOIs | |
State | Published - Mar 26 2021 |
Externally published | Yes |
Keywords
- Computational Medicinal Chemistry
- DNA puckering
- GANT61
- GLI1
- Molecular Dynamics
- Principal Component Analysis
- Zinc finger
- cancer structure-based virtual screening
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
- Pharmacology (medical)