Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor

Radha Charan Dash; Jiachen Wen; Angela M Zaino; Shana R Morel; Lianne Q Chau; Robert J Wechsler-Reya; M Kyle Hadden

doi:10.1016/j.omto.2021.01.004

Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor

Mol Ther Oncolytics. 2021 Jan 16:20:265-276. doi: 10.1016/j.omto.2021.01.004. eCollection 2021 Mar 26.

Authors

Radha Charan Dash¹, Jiachen Wen¹, Angela M Zaino¹, Shana R Morel¹, Lianne Q Chau², Robert J Wechsler-Reya², M Kyle Hadden¹

Affiliations

¹ Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
² Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, 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.

Keywords: Computational Medicinal Chemistry; DNA puckering; GANT61; GLI1; Molecular Dynamics; Principal Component Analysis; Zinc finger; cancer structure-based virtual screening.