1-(3-4-dichlorophenyl)-3-(4-((1-ethyl-3-piperidyl)amino)-6-methyl-2-pyrimidinyl)guanidine and Glioblastoma

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.

Topics: Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Brain Neoplasms; Cell Growth Processes; Cell Survival; Computer Simulation; Drug Design; Glioblastoma; Guanidines; Humans; Mice; Mice, Nude; Molecular Structure; Molecular Targeted Therapy; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Protein Binding; Protein Conformation; Small Molecule Libraries; Tumor Cells, Cultured; Xenograft Model Antitumor Assays