Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumor found in an area of the brainstem called the pons, which controls many of the body?s most vital functions such as breathing, blood pressure, and heart rate. DIPG is the leading cause of pediatric death by brain tumor. Median survival after diagnosis is only 9 months, and 5-year survival is less than 1%. Unfortunately, complete surgical removal is not an option in the treatment of these tumors due to their extensively infiltrative nature and related severe neurological damages to the most vital functions of the body caused by the surgery. The only effective traditional limited-field radiation produces responses in more than 90% of DIPG patients but only transiently. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Numerous trials to increase the dose of radiation have been performed and have not improved patient survival. Thus, new agents that can be used for adjuvant DIPG therapy are desperately needed. Using DIPG cells established from newly diagnosed and recurrent patients, we performed a repurposing drug screen aiming at evaluating the potential of recycling of old known drugs for DIPG therapy. Repurposing drugs that are already approved to treat certain diseases or conditions to see if they are safe and effective for treating other diseases provides quicker translation from bench to bedside. We identified a subset of quinoline class of anti-malaria agents to have significant DIPG killing properties. Among them, we selected the FDA-approved compound mefloquine due to its efficacy and potency in killing all DIPG cells tested with an IC50 <0.5 ?M. Structure activity relationship identified a quinoline analogue with improved efficacy against DIPG cells. Mefloquine remains a useful anti-malarial drug for many patients and is the drug of choice for U.S military deployed overseas; however, a growing body of evidence suggests that mefloquine causes adverse central nervous system effects, due to its high accumulation in the brain. In this proposal, we will take advantage of this unique characteristic of mefloquine and use low dose of this compound or the novel analogue to achieve enough amounts in the brain and target the infiltrative DIPG reservoir, while avoiding the neurological side effects. Investigating the efficiency and safety of mefloquine and analogue in animal models is the first step to move these agents to the clinic to treat DIPG patients.