Grant: Project Grant

Brain cancers represent one of the most aggressive tumors that are especially challenging to treat through drugs. This is partly because the brain is protected by a blood-brain-barrier, which shields the brain from a variety of foreign substances, including several potentially helpful drugs. Therefore, developing drugs that have specific chemical properties that allow them to cross the blood-brain-barrier, while simultaneously retaining their drug-like features is a heavily sought after approach in treating brain cancers. One of the current approaches, is to target a protein called histone deacetylase 6 (HDAC6). HDAC6 has been recently shown to be critical in brain cancer cell development. Although, there are 4 FDA-approved drugs that target HDAC6 on the market, they suffer from at least two limitations. Firstly, they are unselective and target HDAC6 in addition to another 10 HDAC proteins, which leads to severe toxicities in patients. Secondly, they cannot efficiently cross the blood-brain-barrier to target brain cancer cells. Here, we have synthesized small molecule inhibitors that have shown exquisite HDAC6 selectivity (800-fold), and have shown the potential to cross the blood-brain-barrier in mouse models. We aim to expand on our current chemical scaffolds to further develop these properties, and evaluate their efficacy in brain cancer models and help design better treatments.