DDDR-19. NEXT-GENERATION PI3K INHIBITOR FOR GLIOBLASTOMA TREATMENT

Abstract

Abstract High-grade gliomas are especially problematic because of the limited treatment options available to patients. The phosphoinositide 3-kinase (PI3K) pathway has become a significant research target within the field of cancer drug discovery due to the pathway’s promotion of cell proliferation and inhibition of apoptosis. While many new PI3K inhibitory medications show promise in preventing cancer growth, many are toxic because they inhibit multiple PI3K catalytic subunit isoforms making these drugs ineffective treatment options. Our novel peptide drug, Selectide-18, overcomes this toxicity by specifically targeting the p110β isoform of PI3K, which was shown to be the most impactful isoform in many cancer types, including several high-grade gliomas. We designed Selectide-18 after discovering an 18-residue motif unique to p110β. Selectide-18 is a mimetic peptide modeled after this motif. Our in silico analyses show that our drug works by binding to the PI3K regulatory subunit, p85α, thus preventing the binding of catalytic subunit p110β and leaving PI3K inactive. These findings were supported by coimmunoprecipitation. Using a PI3K cell-free kinase assay, we confirmed that our drug specifically targets p110β and does not inhibit p110α, p110δ, or p110γ. The IC50 of Selectide-18 was determined to be approximately 100nM using the same PI3K cell-free kinase assay. We tested several drugs in an MTS viability assay, including Selectide-18, a scrambled 18-residue negative control peptide, and PI3K inhibitor GSK2636771 to compare levels of cancer cell viability. Selectide-18 successfully killed glioblastoma cells within lines with high p110β activity. The drug had no effect in cell lines with low p110β activity. In conclusion, Selectide-18 is explicitly tailored for p110β-high gliomas and has shown promise to treat high-grade glioma effectively. We believe this model of peptide drug can usher in a new generation of p110β specific PI3K inhibitors.