Abstract
Transcription factors (TFs) are a major class of protein signaling molecules that play key cellular roles in cancers such as the highly lethal brain cancer—glioblastoma (GBM). However, the development of specific TF inhibitors has proved difficult owing to expansive protein-protein interfaces and the absence of hydrophobic pockets. We uniquely defined the dimerization surface as an expansive parental pharmacophore comprised of several regional daughter pharmacophores. We targeted the OLIG2 TF which is essential for GBM survival and growth, we hypothesized that small molecules able to fit each subpharmacophore would inhibit OLIG2 activation. The most active compound was OLIG2 selective, it entered the brain, and it exhibited potent anti-GBM activity in cell-based assays and in pre-clinical mouse orthotopic models. These data suggest that (1) our multiple pharmacophore approach warrants further investigation, and (2) our most potent compounds merit detailed pharmacodynamic, biophysical, and mechanistic characterization for potential preclinical development as GBM therapeutics.
Highlights
Transcription factors (TFs) comprise a large class of proteins that bind specific DNA regions and regulate gene expression to control key processes such as differentiation, the cell cycle, survival, and apoptosis [1, 2]
Based on strong homology between OLIG2 and NeuroD1, we modeled the 3D structure of the OLIG2-E47 heterodimer (Homology program, InsightII package, Accelrys, San Diego, CA) using the crystallographic structure of the NeuroD1-E47 heterodimer as a template (PDB ID: 2ql2; Figure 1A; [32])
The development of protein interface pharmacophores has far proved virtually intractable and this reality has limited the development of TF inhibitors [34]
Summary
Transcription factors (TFs) comprise a large class of proteins that bind specific DNA regions and regulate gene expression to control key processes such as differentiation, the cell cycle, survival, and apoptosis [1, 2]. We have previously reported that specific TFs can affect genes related to brain development [5] and potentially impact post-natal brain developmental disorders. Direct inhibition of TFs would ideally involve a small molecule that sufficiently interferes with TF-DNA interaction or with TF-activating dimerization [11]. These two avenues have led to some success. The limited results so far attained suggest that TFs can potentially be directly inhibited
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