Diffuse Intrinsic Pontine Glioma (DIPG) is a high-grade pediatric cancer that develops in the pons of the brain stem. There is no effective treatment for these highly resistant tumors to date, creating a pressing need for new therapeutics. Following the discovery of a mechanism for the reduction of DIPG tumor cell viability via hyperactivation of the ClpP protease, a library of natural products was screened in search of novel ClpP hyperactivators and effective chemotherapeutic agents.