Computational Strategy Finds Brain Tumor-Shrinking Molecules

Computational Strategy Finds Brain Tumor-Shrinking Molecules
These are MRI renderings of mouse brain tumors. Tumors
treated with SKOG102 (lower panels) shrank by about half
compared to tumors treated with a control (upper panels).
Patients with glioblastoma, a type of malignant brain tumor, usually survive fewer than 15 months following diagnosis. Since there are no effective treatments for the deadly disease, University of California, San Diego researchers developed a new computational strategy to search for molecules that could be developed into glioblastoma drugs. In mouse models of human glioblastoma, one molecule they found shrank the average tumor size by half. The study is published by Oncotarget.
 
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.
 
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. In glioblastoma, one misfiring transcription factor called OLIG2 keeps cell growth and survival genes "on" when they shouldn't be, leading to quick-growing tumors.
 
In order to work, transcription factors must buddy up, with two binding to each other and to DNA at same time. If any of these associations are disrupted, the transcription factor is inhibited.
 
In this study, the researchers aimed to disrupt the OLIG2 buddy system as a potential treatment for glioblastoma. Based on the known structure of related transcription factors, they developed a computational strategy to search databases of 3D molecular structures for those small molecules that might engage the hotspot between two OLIG2 transcription factors.
 
With this approach, the researchers identified a few molecules that would likely fit the OLIG2 interaction. They then tested the molecules for their ability to kill glioblastoma tumors. The most effective of these candidate drug molecules, called SKOG102, shrank human glioblastoma tumors grown in mouse models by an average of 50 percent.
 
"While the initial pre-clinical findings are promising," the researchers cautioned, "it will be several years before a potential glioblastoma therapy can be tested in humans. SKOG102 must first undergo detailed pharmacodynamic, biophysical and mechanistic studies in order to better understand its efficacy and possible toxicity."
 
To this end, SKOG102 has been licensed to Curtana Pharmaceuticals, which is currently developing the inhibitor for clinical applications.

Based on material originally posted by University of California - San Diego.