GLI1-Mediated Transcription
GLI1 is a transcription factor that has been identified as a downstream effector for multiple tumorigenic signaling pathways. These include the Hedgehog, RAS-RAF-MEK-ERK, and PI3K-AKT-mTOR pathways, which have all been separately validated as individual anti-cancer drug targets. The identification of GLI1 as a key transcriptional regulator for each of these pathways highlights its promise as a therapeutic target. Small molecule GLI1 inhibitors are potentially efficacious against human malignancies arising from multiple oncogenic mechanisms.
Recent studies have demonstrated that GLI1 regulates a wide-range of oncogenic pathways in multiple forms of cancer. As such, directly targeting this transcription factor is emerging as a strategy to disrupt several tumorigenic signaling mechanisms. We recently identified the 8-hydroxyquinoline chemotype as a small molecule scaffold capable of directly binding to GLI1 and inhibiting GLI1-mediated signaling. Preliminary structure-activity relationship studies have demonstrated regions of the scaffold amenable to modification and provided key insight into the optimal stereochemistry at the chiral center of our lead compound. In addition, we have demonstrated two mechanisms through which the scaffold regulates GLI1-mediated transcriptional activity: (1) direct binding with GLI1 to promote degradation of the protein and (2) inhibition of the GLI1 regulator Src kinase. The overall goal of this proposal is to more fully characterize the mechanisms through which this scaffold inhibits oncogenic GLI1 signaling.