Glioblastoma multiforme (GBM) is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with GBM beyond 14-15 months in part because the blood-brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as GBM treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests GBM cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood-brain barrier. Further investigation in a syngeneic orthotopic mouse model of GBM shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents.
- Received October 19, 2015.
- Revision received May 18, 2016.
- Accepted June 4, 2016.
- Copyright ©2016, American Association for Cancer Research.