5-(4-amino-1-propan-2-yl-3-pyrazolo[3-4-d]pyrimidinyl)-1-3-benzoxazol-2-amine and Brain-Stem-Neoplasms

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKT

Topics: Animals; Apoptosis; Benzoxazoles; Brain Stem Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoradiotherapy; Dose-Response Relationship, Drug; Glioma; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred NOD; Mice, SCID; Multiprotein Complexes; Neoplasm Invasiveness; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Radiation Tolerance; Radiation-Sensitizing Agents; Ribosomal Protein S6 Kinases; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays