Potential Glioblastoma Drug Shrinks Deadly Human Brain Tumors Grown in Mice by Half; Drug Successfully Targets Transient Interface Between Partner Misfiring OLIG2 Transcription Factors to Inhibit Key Binding in the Lethal Cancer

Patients with glioblastoma, a type of malignant brain tumor, usually survive fewer than 15 months following diagnosis. Because there are no effective treatments for this deadly cancer, University of California, San Diego (UCSD) researchers developed a new computational strategy to search for molecules that could be developed into potential glioblastoma drugs. In mouse models of human glioblastoma, one molecule they found shrank the average tumor size by half. The study was published online on October 30, 2015 in an open-access article in Oncotarget. The article is titled “Multiple Spatially Related Pharmacophores Define Small Molecule Inhibitors of OLIG2 in Glioblastoma.” The newly discovered molecule works against glioblastoma by wedging itself in the temporary interface between two proteins whose binding is essential for the tumor's survival and growth. This study is the first to demonstrate successful inhibition of this type of protein, known as a transcription factor. "Most drugs target stable pockets within proteins, so when we started out, people thought it would be impossible to inhibit the transient interface between two transcription factors," said first author Igor Tsigelny, Ph.D., Research Scientist at UC San Diego Moores Cancer Center, as well as the San Diego Supercomputer Center and Department of Neurosciences at UCSD. "But we addressed this challenge and created a new strategy for drug design -- one that we expect many other researchers will immediately begin implementing in the development of drugs that target similar proteins, for the treatment of a variety of diseases." Transcription factors control which genes are turned "on" or "off" at any given time. For most people, transcription factors labor ceaselessly in a highly orchestrated system.
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