EXTH-08. DISCOVERY OF CT-179: A SMALL MOLECULE INHIBITOR OF THE OLIG2 TRANSCRIPTION FACTOR WITH POTENT ANTI-TUMOUR ACTIVITY IN HIGH-GRADE GLIOMA

Abstract

OLIG2 is a protein transcription factor that is expressed exclusively in progenitor cells in the brain and spinal cord during development. Typically, OLIG2 is not active in the adult brain and is not found outside the central nervous system; however, it is re-expressed in most patients with high-grade glioma (HGG). The expression of OLIG2 potentially drives the growth, invasiveness, and resistance to radiation of HGG cells and tumours in animal models. CT-179 is a small molecule (M.W. 397) that, on the basis of homology modelling studies, is a putative disruptor of OLIG2 homodimerization. We found that, at low nanomolar concentrations, CT-179 profoundly inhibited the growth of, and induced apoptosis in, a range of patient-derived HGG cell lines. Approximately half of the HGG cell lines showed substantial degradation of OLIG2 protein, and this was associated with arrest of the cells in the G2/M phase of the cell cycle. We are currently exploring whether this leads to mitotic catastrophe. Additionally, CT-179 caused significant downregulation of receptor tyrosine kinases that are associated with HGG tumorigenicity, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). Orally administered CT-179 (20 mg/kg) crossed the blood-brain barrier of intact mice and reached levels sufficient to inhibit HGG cells. Indeed, the growth of established orthotopic HGG xenografts in mice was significantly inhibited by orally or intraperitoneally administered CT-179, leading to increased survival. CT-179 is one of the few small molecules that has been identified to directly inhibit the function of a transcription factor. Our experiments showing the profound anti-tumour activity of CT-179 in HGG models pro vide the impetus needed for moving this molecule into the clinic as a novel therapy for patients with HGG.