Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor
| Autor: | M. Kyle Hadden, Shana R. Morel, Lianne Q. Chau, Robert J. Wechsler-Reya, Radha Charan Dash, Angela M. Zaino, Jiachen Wen |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research GLI1 cancer structure-based virtual screening Molecular Dynamics lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Transcription (biology) Zinc finger Transcriptional regulation Pharmacology (medical) DNA puckering GANT61 Transcription factor Virtual screening Principal Component Analysis biology integumentary system Chemistry Computational Medicinal Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Small molecule Cell biology 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Molecular Medicine Original Article Signal transduction |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 20, Iss, Pp 265-276 (2021) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | 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. Graphical Abstract 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. |
| Databáze: | OpenAIRE |
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