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Published on: September 13, 2022
Multiple spatially related pharmacophores define small molecule inhibitors of OLIG2 in glioblastoma
Igor F Tsigelny1,2,3, Rajesh Mukthavaram3, Valentina L Kouznetsova2,3
1Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
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.
Insights
Researchers developed a novel approach to target transcription factors (TFs) in glioblastoma (GBM). A new selective OLIG2 inhibitor demonstrated potent anti-GBM activity in preclinical models, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Transcription factors (TFs) are crucial signaling molecules in cancer, including glioblastoma (GBM).
- Developing specific TF inhibitors is challenging due to large protein interfaces and lack of pockets.
- OLIG2 TF is essential for GBM survival and proliferation.
Purpose of the Study:
- To develop a novel therapeutic strategy targeting the OLIG2 transcription factor in GBM.
- To identify small molecules that inhibit OLIG2 activation using a unique pharmacophore approach.
Main Methods:
- Defined the dimerization surface of OLIG2 as a multi-pharmacophore.
- Designed and screened small molecules to fit subpharmacophores of OLIG2.
- Evaluated compound selectivity, brain penetration, and anti-GBM activity in vitro and in vivo.
Main Results:
- Identified an OLIG2-selective compound with potent anti-GBM activity.
- The compound successfully penetrated the brain.
- Demonstrated significant anti-GBM effects in cell-based assays and preclinical mouse models.
Conclusions:
- The multi-pharmacophore approach is a viable strategy for TF inhibition.
- The developed OLIG2 inhibitors show potential for preclinical development as GBM therapeutics.
- Further characterization of lead compounds is warranted for clinical translation.
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