Dash Radha Charan, Wen Jiachen, Zaino Angela M, Morel Shana R, Chau Lianne Q, Wechsler-Reya Robert J, Hadden M Kyle
Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd., Unit 3092, Storrs, CT 06269-3092, USA.
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.
Mol Ther Oncolytics. 2021 Jan 16;20:265-276. doi: 10.1016/j.omto.2021.01.004. eCollection 2021 Mar 26.
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 , which is an 8-hydroxyquinoline, as a high-affinity binder of GLI1. Compound 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 inhibits GLI1 function after binding. Our results strongly suggest that binding of 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.
胶质瘤相关转录因子家族（GLI）已成为多种人类癌症颇具前景的治疗靶点。特别是，GLI1作为多种致癌信号通路（包括刺猬信号通路（Hh））的转录调节因子发挥核心作用。我们采用了一种计算筛选方法来鉴定直接结合GLI1的小分子，以开发其作为GLI介导转录的抑制剂。通过这些研究，我们鉴定出化合物 ，它是一种8-羟基喹啉，是GLI1的高亲和力结合剂。化合物 在几种Hh依赖的细胞模型中抑制GLI1介导的转录活性，包括小鼠髓母细胞瘤的原代模型。我们还进行了一系列计算分析，以更清楚地确定 结合后抑制GLI1功能的机制。我们的结果强烈表明， 与GLI1的结合不会阻止GLI1/DNA结合，也不会破坏GLI1/DNA复合物，相反，它会在整个复合物中诱导特定的构象变化，从而阻止GLI正常发挥功能。这些结果突出了该化合物作为靶向GLI1的抗癌药物进一步开发的潜力。
