Development of novel histone demethylase inhibitor against dipg

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of most the devastating pediatric brain tumors, and virtually all patients die within two years after diagnosis. It has been shown that targeted inhibition of JMJD3 demethylase activity by GSK-J4 results in restored K27 methylation and a significant delay of tumor progression and prolonged animal survival in intracranial DIPG patient-derived xenograft (PDX) models. Because of its promising anti-tumor activities, GSK-J4 has been used to treat many kinds of tumors in preclinical models including leukemia, lymphoma, neuroblastoma, prostate, and gastric cancer, and DIPG; however, GSK-J4 is not yet in clinical development. The major challenge for GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted in vivo to the active drug GSK-J1, which has restricted cellular and brain permeability. Hypothesis: We hypothesize that development of a stable GSK- J1 analog that offers good cellular and brain transport is essential to improving in vivo efficacy and is required for clinical application of this class of compounds. METHODS We developed a novel alcohol derivative of GSK-J1, UR-8, as a lead anti-cancer agent through our screening and drug development activities. RESULTS UR-8 has demonstrated selective cytotoxic activity against human K27M DIPG cells in vitro and apparently transported the brain to a useful extent based on its in vivo bio-distribution and effectiveness. CONCLUSION UR-8 showed greater anti-tumor activity and survival benefit than that obtained by GSK-J4 treatment in intracranial DIPG PDX models.